Novel rock inhibitors

ABSTRACT

The present invention relates to new kinase inhibitors, more specifically ROCK inhibitors, compositions, in particular pharmaceuticals, comprising such inhibitors, and to uses of such inhibitors in the treatment and prophylaxis of disease. In particular, the present invention relates to new ROCK inhibitors, compositions, in particular pharmaceuticals, comprising such inhibitors, and to uses of such inhibitors in the treatment and prophylaxis of disease. In addition, the invention relates to methods of treatment and use of said compounds in the manufacture of a medicament for the application to a number of therapeutic indications including sexual dysfunction, inflammatory diseases, ophthalmic diseases and Respiratory diseases.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. patent application Ser. No.13/582,195 filed Aug. 31, 2012, entitled HETEROCYCLIC AMIDES AS ROCKINHIBITORS, which application is a national phase entry ofPCT/EP11/53343 filed Mar. 4, 2011, which claims priority to GreatBritain Application No. 1003395.9 filed Mar. 2, 2010 and Great BritainApplication No. 1018996.7 filed Nov. 10, 2010. The entire contents ofsaid application is hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to new kinase inhibitors, morespecifically ROCK inhibitors, compositions, in particularpharmaceuticals, comprising such inhibitors, and to uses of suchinhibitors in the treatment and prophylaxis of disease. In particular,the present invention relates to new ROCK inhibitors, compositions, inparticular pharmaceuticals, comprising such inhibitors, and to uses ofsuch inhibitors in the treatment and prophylaxis of disease.

BACKGROUND OF THE INVENTION

The serine/threonine protein kinase ROCK consists in humans of twoisoforms ROCK I and ROCK II. ROCK I is encoded on chromosome 18 whereasROCK II, also called Rho-kinase, is located on chromosome 12. They bothhave a molecular weight close to 160 kDa. They share an overall homologyof 65% while being 95% homologous in their kinase domains. Despite theirsequence similarity, they differ by their tissue distributions. Thehighest levels of expression for ROCK I are observed in heart, lung andskeletal tissues whereas ROCK II is mostly expressed in brain. Recentdata indicate that these two isoforms are partially function redundant,ROCK I being more involved in immunological events, ROCK II in smoothmuscle function. The term ROCK refers to ROCK I (aka ROK-β, p 160ROCK,or Rho-kinase β) and ROCK II (aka ROCK-α or Rho-kinase α).

ROCK activity has been shown to be enhanced by GTPase RhoA that is amember of the Rho (Ras homologous) GTP-binding proteins. The activeGTP-bound state of RhoA interacts with Rho-binding domain (RBD) of ROCKthat is located in an autoinhibitory carboxyl-terminal loop. Uponbinding, the interactions between the ROCK negative regulatory domainand the kinase domain are disrupted. The process enables the kinase toacquire an open conformation in which it is fully active. The openconformation is also induced by the binding of lipid activators such asarachidonic acid to the PH domain in the kinase carboxyl-terminaldomain. Another activation mechanism has been described during apoptosisand involves the cleavage of carboxyl terminus by caspase-3 and -2 (orgranzyme B) for ROCK I and II, respectively.

ROCK plays an important role in various cellular functions such assmooth muscle contraction, actin cytoskeleton organization, plateletactivation, downregulation of myosin phosphatase cell adhesion,-migration, -proliferation and survival, thrombin-induced responses ofaortic smooth muscle cells, hypertrophy of cardiomyocytes, bronchialsmooth muscle contraction, smooth muscle contraction and cytoskeletalreorganization of non-muscle cells, activation of volume-regulated anionchannels, neurite retraction, wound healing, cell transformation andgene expression. ROCK also acts in several signaling pathways that areinvolved in auto-immunity and inflammation. ROCK has been shown to playa part in the activation of NF-κB, a critical molecule that leads to theproduction of TNF and other inflammatory cytokines. ROCK inhibitors arereported to act against TNF-alpha and IL-6 production inlipopolysaccharide (LPS)-stimulated THP-1 macrophages. Therefore, ROCKinhibitors provide a useful therapy to treat autoimmune and inflammatorydiseases as well as oxidative stress.

In conclusion, ROCK is a major control point in smooth muscle cellfunction and a key signaling component involved in inflammatoryprocesses in various inflammatory cells as well as fibrosis andremodeling in many diseased organs. There are clear indications thatROCK is involved in the pathogenesis of many diseases, including asthma,COPD and glaucoma. In addition, ROCK has been implicated in variousdiseases and disorders including eye diseases; airway diseases;cardiovascular and vascular diseases; inflammatory diseases;neurological and CNS disorders: proliferative diseases; kidney diseases;sexual dysfunction; blood diseases; bone diseases; diabetes; benignprostatic hyperplasia, transplant rejection, liver disease, systemiclupus erythematosus, spasm, hypertension, chronic obstructive bladderdisease, premature birth, infection, allergy, obesity, pancreaticdisease and AIDS.

ROCK appears to be a safe target, as exemplified by knockout models anda large number of academic studies. These KO mice data, in combinationwith post-marketing surveillance studies with Fasudil, a moderatelypotent ROCK inhibitor used for the treatment of vasospasm aftersubarachnoid hemorrhage, indicate that ROCK is a genuine and significantdrug target.

ROCK inhibitors would be useful as therapeutic agents for the treatmentof disorders implicated in the ROCK pathway. Accordingly, there is agreat need to develop ROCK inhibitors that are useful in treatingvarious diseases or conditions associated with ROCK activation,particularly given the inadequate treatments currently available for themajority of these disorders. Some non-limiting examples are glaucoma,asthma and COPD.

Glaucoma, a group of diseases that may cause vision loss and blindnessdue to damage of the optic nerve, is caused by increased intra-ocularpressure. It is a common cause of adult blindness, mostly a chronicdisease that requires life-long control after diagnosis. There is a needfor improved treatment as the current therapy does only control and notcure the disease and further suffers from irritation, local and systemicside effects. In addition, additional positive effects, as theanti-inflammatory and nerve regenerating components of ROCK inhibitors,would be highly preferred. Reference ROCK inhibitors, such as Y-27632cause changes in cell shape and decrease stress fibers, focal adhesionsand MLC phosphorylation in cultured human TM cells; they relax humantrabecular meshwork in vitro, relax human Schlemm's canal endothelialcells in vitro and when topically applied to animals give a significantincrease in trabecular outflow, resulting into a strong lowering ofintra ocular pressure.

Allergic asthma is a chronic inflammatory airway disorder that resultsfrom maladaptive immune responses to ubiquitous environmental proteinsin genetically susceptible persons. Despite reasonably successfultherapies, the prevalence increases as these therapies do not cure;there are still exacerbations and an increasing number ofnon-responders. New, effective and steroid-sparing treatments thattackle all components of the disease are required.

Chronic Obstructive Pulmonary Disease (COPD) represents a group ofdiseases characterized by irreversible limitation of airflow, associatedwith abnormal inflammatory response, bronchoconstriction and remodelingand destruction of the tissue of the lung. It is one of the leadingcauses of death worldwide, with a steadily increasing prevalence. Thereis an urgent need for novel therapeutic approaches as the currentregimen is inadequate. Until now only bronchodilators are used, sinceglucocorticoids have limited or no effect. Reference ROCK inhibitors,such as Y-27632 relax human isolated bronchial preparations, inhibitincreases in airway resistance in anaesthetised animals, potentiaterelaxing effects of β-agonists in vitro and in vivo and give rapidbronchodilatation upon inhalation. In addition, ROCK inhibitors blocktracheal smooth muscle contractions induced by H₂O₂, the clinical markerfor oxidative stress.

Related to airway inflammation, ROCK inhibitors counteract the increasein trans-endothelial permeability mediated by inflammatory agents,maintain the endothelial barrier integrity, inhibit the influx ofeosinophils after ovalbumin challenge in vivo, protect against lungedema formation and neutrophile migration, suppress airway HR tometacholine and serotonin in allergic mice and block LPS-induced TNFrelease. With respect to airway fibrosis and remodeling, ROCK inhibitorsblock the induced migration of airway smooth muscle cells. In vitroevidences for the role of ROCK in airway remodeling were obtained inhuman lung carcinoma cell line, bovine tracheal smooth muscle cells andhuman airway smooth muscle. In vivo proof for a role of ROCK in fibrosisin general was generated with mice which exhibited attenuated myocardialfibrosis in response to the partial deletion of ROCK. The attenuation ofmyocardial fibrosis by Y-27632 in response to myocardial infarction andby fasudil in the case of congestive heart failure in a chronichypertensive rat model brings additional indications of ROCK importancein remodeling. Finally, ROCK inhibitors increase apoptotic cell loss ofsmooth muscle cells.

The human sexual response in both males and females results from aninterplay of physiological, psychological, and hormonal factors. Onecommon aspect of the sexual response in males and females, however, isthe vasoactive response, which results in engorgement of the sexualtissues of the genitalia with blood as a result of vascular smoothmuscle relaxation in response to sexual stimulation. Thus, bloodpressure and blood flow inside the penis and clitoris increase whensmooth muscles of the pudental vasculature relax. This arterial influxof blood causes enlargement of the penile or clitoral corpora cavernosaand results in erection.

Impotence (erectile dysfunction in men) is generally defined as aninability to achieve and sustain an erection sufficient for satisfactorysexual performance and intercourse. Impotence can be due topsychological disturbances, neurological abnormalities, or otherphysiological disturbances including hormonal deficiencies or, acombination of causes. In the United States, male impotence is estimatedto affect 40% of men at age 40, increasing with age to about 50% by 50years, and is as high as 67% by the age of 70. It is estimated that upto 30 million males may suffer from impotence in the U.S.

Females can also have sexual dysfunction that increases with age and isassociated with the onset of menopause and increased risk of vasculardisorders. Thus, similar to men, sexual arousal in women is accompanied,at least in part, by increased blood flow which engorges the clitoris.Blood flow to the vagina also increases vaginal lubrication. Thus,female sexual dysfunction can result from an inability to attain ormaintain clitoral engorgement and/or vaginal lubrication throughout theperiod of sexual activity.

Currently, most vasodilators used to treat erectile dysfunction targetsignal transduction pathways that reduce calcium ion, which is needed toinitiate contractile activity in vascular smooth muscle. However, from aphysiological standpoint, the initiation of vasoconstriction is a veryacute event lasting only seconds to a few minutes. The erectile tissueis maintained in the flaccid state by long-term vasoconstriction througha signal transduction pathway that is calcium-independent. A signalpathway that maintains calcium-independent vasoconstriction is theRhoA/Rho-kinase pathway. ROCK inhibitors are accordingly useful to treaterectile dysfunction. Thus, in one aspect, the present inventioncomprises a method for treating male or female sexual dysfunction whichcomprises topical administration to an individual in need thereof of acomposition comprising a compound which attenuates Rho-kinase activityin an organ subject to sexual stimulation, and a pharmaceuticallyacceptable carrier.

Several different classes of ROCK inhibitors are known. The currentfocus is oncology and cardiovascular applications. Until now, theoutstanding therapeutic potential of ROCK inhibitors has only beenexplored to a limited extent. The reason is the fact that ROCK is such apotent and widespread biochemical regulator, that systemic inhibition ofROCK leads to strong biological effects that are considered as beingside effects for the treatment of most of the diseases. Indeed, themedical use of ROCK inhibitors to treat diseases with a stronginflammatory component is hampered by the pivotal role of ROCK in theregulation of the tonic phase of smooth muscle cell contraction.Systemically available ROCK inhibitors induce a marked decrease in bloodpressure. Therefore, ROCK inhibitors with different properties arehighly required.

For the target specific treatment of disorders by regulating smoothmuscle function and/or inflammatory processes and/or remodeling, it ishighly desired to deliver a ROCK inhibitor to the target organ and toavoid significant amounts of these drugs to enter other organs.Therefore, local or topical application is desired. Typically, topicaladministration of drugs has been applied for the treatment of airway-,eye, sexual dysfunction and skin disorders. In addition, localinjection/infiltration into diseased tissues further extend thepotential medical use of locally applied ROCK inhibitors. Given certaincriteria are fulfilled, these local applications allow high drugconcentration to be reached in the target tissue. In addition, theincorporation of ROCK inhibitors into implants and stents can furtherexpand the medical application towards the local treatment of CVdiseases such as atherosclerosis, coronary diseases and heart failure.

Despite the fact that direct local application is preferred in medicalpractice, there are concerns regarding drug levels reached into thesystemic circulation. For example the treatment of airway diseases bylocal delivery by for instance inhalation, poses the risk of systemicexposure due to large amounts entering the GI tract and/or systemicabsorption through the lungs. For the treatment of eye diseases by localdelivery, also significant amounts enter the GI tract and/or systemiccirculation due to the low permeability of the cornea, low capacity forfluid, efficient drainage and presence of blood vessels in the eyelids.Also for dermal applications, local injections and implantable medicaldevices, there is a severe risk of leakage into the systemiccirculation. Therefore, in addition to local application, the compoundsshould preferably have additional properties to avoid significantsystemic exposure.

Soft drugs are biologically active compounds that are inactivated oncethey enter the systemic circulation. This inactivation can be achievedin the liver, but the preferred inactivation should occur in the blood.These compounds, once applied locally to the target tissue/organ exerttheir desired effect locally. When they leak out of this tissue into thesystemic circulation, they are very rapidly inactivated. Thus, softdrugs of choice are sufficiently stable in the target tissue/organ toexert the desired biological effect, but are rapidly degraded in theblood to biologically inactive compounds. In addition, it is highlypreferable that the soft drugs of choice have retention at theirbiological target. This property will limit the number of dailyapplications and is highly desired to reduce the total load of drug andmetabolites and in addition will significantly increase the patientcompliance.

In conclusion, there is a continuing need to design and develop softROCK inhibitors for the treatment of a wide range of disease states. Thecompounds described herein and pharmaceutically acceptable compositionsthereof are useful for treating or lessening the severity of a varietyof disorders or conditions associated with ROCK activation. Morespecifically, the compounds of the invention are preferably used in theprevention and/or treatment of at least one disease or disorder, inwhich ROCK is involved, such as diseases linked to smooth muscle cellfunction, inflammation, fibrosis, excessive cell proliferation,excessive angiogenesis, hyperreactivity, barrier dysfunction,neurodegeneration and remodeling. For example, the compounds of theinvention may be used in the prevention and/or treatment of diseases anddisorders such as:

Eye diseases or disorders: including but not limited to retinopathy,optic neuropathy, glaucoma and degenerative retinal diseases such asmacular degeneration, retinitis pigmentosa and inflammatory eyediseases.

Airway diseases; including but not limited to pulmonary fibrosis,emphysema, chronic bronchitis, asthma, fibrosis, pneumonia, cysticfibrosis, chronic obstructive pulmonary disease (COPD); bronchitis andrhinitis and respiratory distress syndrome

Throat, Nose and Ear diseases: including but not limited to sinusproblems, hearing problems, toothache, tonsillitis, ulcer and rhinitis,

Skin diseases: including but not limited to hyperkeratosis,parakeratosis, hypergranulosis, acanthosis, dyskeratosis, spongiosis andulceration.

Intestinal diseases; including but not limited to inflammatory boweldisease (IBD), colitis, gastroenteritis, ileus, ileitis, appendicitisand Crohn's disease.

Cardiovascular and vascular diseases: including but not limited to,pulmonary hypertension and pulmonary vasoconstriction.

Inflammatory diseases: including but not limited to contact dermatitis,atopic dermatitis, psoriasis, rheumatoid arthritis, juvenile rheumatoidarthritis, ankylosing spondylitis, psoriatic arthritis, inflammatorybowel disease, Crohn's disease and ulcerative colitis.

Neurological disorders: including but not limited to neuropathic pain.The present compounds are therefore suitable for preventingneurodegeneration and stimulating neurogeneration in variousneurological disorders.

Proliferative diseases: such as but not limited to cancer of, breast,colon, intestine, skin, head and neck, nerve, uterus, kidney, lung,ovary, pancreas, prostate, or thyroid gland; Castleman disease;leukemia; sarcoma; lymphoma; malignoma; and melanoma.

Kidney diseases: including but not limited to renal fibrosis or renaldysfunction.

Sexual dysfunction: is meant to include both male and female sexualdysfunction caused by a defective vasoactive response. The soft ROCKinhibitors of the present invention may also be used to treat sexualdysfunction arising from a variety of causes. For example, in anembodiment, the soft ROCK inhibitors may be used to treat sexualdysfunction associated with hypogonadism and more particularly, whereinthe hypogonadism is associated with reduced levels of androgen hormones.In another embodiment, the soft ROCK inhibitors may be used to treatsexual dysfunction associated with a variety of causes including, butnot limited to, bladder disease, hypertension, diabetes, or pelvicsurgery. In addition, the soft ROCK inhibitors may be used to treatsexual dysfunction associated with treatment using certain drugs, suchas drugs used to treat hypertension, depression or anxiety.

Bone diseases: including but not limited to osteoporosis andosteoarthritis.

In addition, the compounds of the invention may be used in theprevention and/or treatment of diseases and disorders such as benignprostatic hyperplasia, transplant rejection, spasm, chronic obstructivebladder disease, and allergy.

SUMMARY OF THE INVENTION

We have surprisingly found that the compounds described herein act asinhibitors of ROCK, in particular as soft ROCK inhibitors. Compared toart known Rock inhibitors, such as for example described inWO2007/042321, the compounds of the present invention differ in thatthey are very rapidly converted into functionally inactive compoundssuch as for example by Paraoxonase 1 (PON1) activity.

PON1 is a Ca2+ dependent serum class A-esterase, which is synthesized inthe liver and secreted in the blood, where it associates exclusivelywith high-density lipoproteins (HDLs). Furthermore, it is able to cleavea unique subset of substrate including organophosphates, arylesters,lactones and cyclic carbonates. Therefore, the Y substituent of thecompounds of the present invention, generally represented by formula Ihereinbelow, are selected to comprise a substituent selected from thegroup of arylesters, lactones and cyclic carbonates, more specificallyfrom arylesters and lactones.

Unless a context dictates otherwise, asterisks are used herein toindicate the point at which a mono- or bivalent radical depicted isconnected to the structure to which it relates and of which the radicalforms part.

Viewed from a first aspect, the invention provides a compound of FormulaI or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug,salt, hydrate, or solvate thereof,

Wherein

R¹ is selected form the group comprising hydrogen, alkyl or cycloalkyl;

Ar is selected from the group comprising:

Wherein X is selected from the group comprising hydrogen or halo;

Y is an aryl or heteroaryl substituted with a substituent selected fromthe group consisting of —C(═O)—OR²¹; —C(═O)—SR²²; —C(═O)—NR³R⁴; —NR⁵R⁶;—O—C₁₋₆alkyl; —S—C₁₋₆alkyl; —O—C₂₋₈alkenyl; —S—C₂₋₈alkenyl; —C₁₋₆alkyl;or —C₂₋₈alkenyl;

-   -   wherein said —O—C₁₋₆alkyl; —S—C₁₋₆alkyl; —O—C₂₋₈alkenyl;        —S—C₂₋₈alkenyl; —C₁₋₆alkyl; or —C₂₋₈alkenyl; are each        independently substituted with a substituent selected from the        group consisting of C(═O)—OR²¹; —C(═O)—SR²²; —C(═O)—NR³R⁴; Het¹;        —O-Het²; and —S-Het³;

R³ is selected from the group consisting of hydrogen; C₂₋₈alkenylsubstituted with O-Het² or —S-Het³; or C₁₋₂₀alkyl optionally substitutedwith 1, 2 or 3 substituents each independently selected from the groupconsisting of aryl, heteroaryl, C₃₋₆cycloalkenyl, —C(═O)—OR²¹,—C(═O)—SR²², —C(═O)—NR⁷R⁸, Het¹, —O-Het², —S-Het³, —S—C₁₋₆alkyl and—O—C₁₋₆alkyl;

-   -   wherein said —O—C₁₋₆alkyl; —S—C₁₋₆alkyl; or C₃₋₆cycloalkenyl;        are each independently substituted with a substituent selected        from the group consisting of C(═O)—OR²¹; —C(═O)—SR²²;        —C(═O)—NR³R⁴; Het¹; —O-Het²; and —S-Het³;

R⁴ is selected from the group consisting of C₂₋₈alkenyl substituted withO-Het² or —S-Het³; or C₁₋₂₀alkyl optionally substituted with 1, 2 or 3substituents each independently selected from the group consisting ofaryl, heteroaryl, C₃₋₆cycloalkenyl, —C(═O)—OR²¹, —C(═O)—SR²²,—C(═O)—NR⁷R⁸, Het¹, —O-Het², —S-Het³, —O—C₁₋₆alkyl and —O—S₁₋₆alkyl;

-   -   wherein said —O—C₁₋₆alkyl; —S—C₁₋₆alkyl; or C₃₋₆cycloalkenyl;        are each independently substituted with a substituent selected        from the group consisting of C(═O)—OR²¹; —C(═O)—SR²²;        —C(═O)—NR³R⁴; Het¹; —O-Het²; and —S-Het³; or;

R³ and R⁴ together with the nitrogen atom to which they are attachedform a heterocycle substituted with one substituent selected from thegroup consisting of —C(═O)—OR²¹; —C(═O)—SR²²; —C(═O)—NR⁹R¹⁰; Het¹;—O-Het²; —S-Het³; C₁₋₆alkyl; C₁₋₆alkyl-O—C₁₋₄alkyl; orC₁₋₆alkyl-O—C₂₋₄alkenyl; wherein each of said C₁₋₆alkyl;C₁₋₆alkyl-O—C₁₋₄alkyl; or C₁₋₆alkyl-O—C₂₋₄alkenyl is each independentlysubstituted with 1, 2, or 3 substituents each independently selectedfrom the group consisting of aryl, heteroaryl, C₃₋₆cycloalkenyl,—C(═O)—OR²¹; —C(═O)—SR²²; —C(═O)—NR⁹R¹⁰; Het¹; —O-Het²; and —S-Het³;

R⁵ or R⁶ are independently selected from the group consisting ofhydrogen; C₁₋₆alkyl; C₁₋₆alkyl-O—C₁₋₆alkyl-; C₁₋₆alkyl-S—C₁₋₆alkyl-;C₂₋₈alkenyl; C₁₋₆alkyl-C(═O)— or C₂₋₈alkenyl-C(═O)—; wherein at leastone of R⁵ or R⁶ is selected from C₁₋₆alkyl; C₁₋₆alkyl-O—C₁₋₆alkyl-;C₁₋₆alkyl-S—C₁₋₆alkyl-; C₂₋₈alkenyl; C₁₋₆alkyl-C(═O)— orC₂₋₆alkenyl-C(═O)—, and wherein each of said C₁₋₆alkyl;C₁₋₆alkyl-O—C₁₋₆alkyl-; C₁₋₆alkyl-S—C₁₋₆alkyl-; C₂₋₈alkenyl;C₁₋₆alkyl-C(═O)— or C₂₋₈alkenyl-C(═O)— is substituted with 1, 2, or 3substituents each independently selected from the group consisting ofaryl, heteroaryl, C₃₋₆cycloalkenyl, —C(═O)—OR²¹; —C(═O)—SR²²; Het¹;—O-Het²; and —S-Het³;

R⁷ or R⁸ are independently selected from the group consisting ofhydrogen; or C₁₋₆alkyl substituted with 1, 2, or 3 substituents eachindependently selected from the group consisting of aryl, heteroaryl,C₃₋₆cycloalkenyl, —C(═O)—OR²; and —C(═O)—NH₂;

R⁹ or R¹⁰ are independently selected from the group consisting ofhydrogen; or C₁₋₆alkyl substituted with 1, 2, or 3 substituents eachindependently selected from the group consisting of aryl, heteroaryl,C₃₋₆cycloalkenyl, —C(═O)—OR²¹; and —C(═O)—NH₂;

R¹³ or R¹⁴ are independently selected from the group consisting ofhydrogen; C₁₋₆alkyl; C₁₋₆alkyl; C₁₋₆alkyl-O—C₁₋₆alkyl-;C₁₋₆alkyl-S—C₁₋₆alkyl-; or C₁₋₆alkyl-C(═O)— and wherein each of saidC₁₋₆alkyl; C₁₋₆alkyl-O—C₁₋₆alkyl-; C₁₋₆alkyl-S—C₁₋₆alkyl-; orC₁₋₆alkyl-C(═O)— is substituted with 1, 2, or 3 substituents eachindependently selected from the group consisting of —C(═O)—OR²¹;—C(═O)—SR²²; Het¹; —O-Het²; and —S-Het³;

R²¹ is selected from the group consisting of C₁₋₂₀alkyl; C₁₋₂₀alkenyl;C₁₋₂₀alkynyl; optionally substituted C₃₋₁₅cycloalkyl; optionallysubstituted aryl; optionally substituted heterocyclyl; and optionallysubstituted heteroaryl;

-   -   wherein said C₁₋₂₀alkyl is optionally substituted with 1, 2, 3        or more substituents each independently selected from the group        consisting of halo, cyano, hydroxy, aryl-O—, aryl-S—,        aryl-S(═O)₂—, aryl-C(═O), —C(═O)—NR¹³R¹⁴, C₃₋₁₀cycloalkyl,        —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl-O—, C₁₋₆alkyl-S—, aryl,        heteroaryl, heterocyclyl or from the formula:

or

R²¹ taken together with the oxycarbonyl and ‘aryl or heteroaryl’ towhich it is attached forms a cyclic ester comprising from 4 to 9 carbonatoms in the cyclic ester ring;

R²² is C₁₋₂₀alkyl optionally substituted with 1, 2, 3 or moresubstituents each independently selected from the group consisting ofhalo, hydroxy, amino, cyano, and mono- or di-(C₁₋₄alkyl)amino;

Het¹, Het² or Het³ are independently selected from the group comprising;

Viewed from a further aspect, the invention provides the use of acompound of the invention, or a composition comprising such a compound,for inhibiting the activity of at least one kinase, in vitro or in vivo.

Viewed from a further aspect, the invention provides the use of acompound of the invention, or a composition comprising such a compound,for inhibiting the activity of at least one ROCK kinase, for exampleROCKII and/or ROCKI isoforms.

Viewed from a further aspect, the invention provides a pharmaceuticaland/or veterinary composition comprising a compound of the invention.

Viewed from a still further aspect, the invention provides a compound ofthe invention for use in human or veterinary medicine.

Viewed from a still further aspect, the invention provides the use of acompound of the invention in the preparation of a medicament for theprevention and/or treatment of at least one disease and/or disorderselected from the group comprising eye diseases; airway diseases;cardiovascular and vascular diseases; inflammatory diseases;neurological and CNS disorders: proliferative diseases; kidney diseases;sexual dysfunction; blood diseases; bone diseases; diabetes; benignprostatic hyperplasia, transplant rejection, liver disease, systemiclupuserythematosus, spasm, hypertension, chronic obstructive bladderdisease, premature birth, infection, allergy, obesity, pancreaticdisease and AIDS.

DETAILED DESCRIPTION OF THE INVENTION

The present invention will now be further described. In the followingpassages, different aspects of the invention are defined in more detail.Each aspect so defined may be combined with any other aspect or aspectsunless clearly indicated to the contrary. In particular, any featureindicated as being preferred or advantageous may be combined with anyother feature or features indicated as being preferred or advantageous.

Unless a context dictates otherwise, asterisks are used herein toindicate the point at which a mono- or bivalent radical depicted isconnected to the structure to which it relates and of which the radicalforms part.

Undefined (racemic) asymmetric centers that may be present in thecompounds of the present invention are interchangeably indicated bydrawing a wavy bonds or a straight bond in order to visualize theundefined steric character of the bond.

As already mentioned hereinbefore, in a first aspect the presentinvention provides compounds of Formula I

wherein Y, R¹ and Ar are as defined hereinbefore, including thestereo-isomeric forms, solvates, and pharmaceutically acceptableaddition salts thereof.

When describing the compounds of the invention, the terms used are to beconstrued in accordance with the following definitions, unless a contextdictates otherwise:

The term “alkyl” by itself or as part of another substituent refers to afully saturated hydrocarbon of Formula C_(x)H_(2x+1) wherein x is anumber greater than or equal to 1. Generally, alkyl groups of thisinvention comprise from 1 to 20 carbon atoms. Alkyl groups may be linearor branched and may be substituted as indicated herein. When a subscriptis used herein following a carbon atom, the subscript refers to thenumber of carbon atoms that the named group may contain. Thus, forexample, C₁₋₄alkyl means an alkyl of one to four carbon atoms. Examplesof alkyl groups are methyl, ethyl, n-propyl, i-propyl, butyl, and itsisomers (e.g. n-butyl, i-butyl and t-butyl); pentyl and its isomers,hexyl and its isomers, heptyl and its isomers, octyl and its isomers,nonyl and its isomers; decyl and its isomers. C₁-C₆ alkyl includes alllinear, branched, or cyclic alkyl groups with between 1 and 6 carbonatoms, and thus includes methyl, ethyl, n-propyl, i-propyl, butyl andits isomers (e.g. n-butyl, i-butyl and t-butyl); pentyl and its isomers,hexyl and its isomers, cyclopentyl, 2-, 3-, or 4-methylcyclopentyl,cyclopentylmethylene, and cyclohexyl.

The term “optionally substituted alkyl” refers to an alkyl groupoptionally substituted with one or more substituents (for example 1 to 4substituents, for example 1, 2, 3, or 4 substituents or 1 to 2substituents) at any available point of attachment. Non-limitingexamples of such substituents include halo, hydroxyl, carbonyl, nitro,amino, oxime, imino, azido, hydrazino, cyano, aryl, heteroaryl,cycloalkyl, acyl, alkylamino, alkoxy, thiol, alkylthio, carboxylic acid,acylamino, alkyl esters, carbamate, thioamido, urea, sullfonamido andthe like.

The term “alkenyl”, as used herein, unless otherwise indicated, meansstraight-chain, cyclic, or branched-chain hydrocarbon radicalscontaining at least one carbon-carbon double bond. Examples of alkenylradicals include ethenyl, E- and Z-propenyl, isopropenyl, E- andZ-butenyl, E- and Z-isobutenyl, E- and Z-pentenyl, E- and Z-hexenyl,E,E-, E,Z-, Z,E-, Z,Z-hexadienyl, and the like. An optionallysubstituted alkenyl refers to an alkenyl having optionally one or moresubstituents (for example 1, 2, 3 or 4), selected from those definedabove for substituted alkyl.

The term “alkynyl”, as used herein, unless otherwise indicated, meansstraight-chain or branched-chain hydrocarbon radicals containing atleast one carbon-carbon triple bond. Examples of alkynyl radicalsinclude ethynyl, E- and Z-propynyl, isopropynyl, E- and Z-butynyl, E-and Z-isobutynyl, E- and Z-pentynyl, E, Z-hexynyl, and the like. Anoptionally substituted alkynyl refers to an alkynyl having optionallyone or more substituents (for example 1, 2, 3 or 4), selected from thosedefined above for substituted alkyl.

The term “cycloalkyl” by itself or as part of another substituent is acyclic alkyl group, that is to say, a monovalent, saturated, orunsaturated hydrocarbyl group having 1, 2, or 3 cyclic structure.

Cycloalkyl includes all saturated or partially saturated (containing 1or 2 double bonds) hydrocarbon groups containing 1 to 3 rings, includingmonocyclic, bicyclic, or polycyclic alkyl groups. Cycloalkyl groups maycomprise 3 or more carbon atoms in the ring and generally, according tothis invention comprise from 3 to 15 atoms. The further rings ofmulti-ring cycloalkyls may be either fused, bridged and/or joinedthrough one or more spiro atoms. Cycloalkyl groups may also beconsidered to be a subset of homocyclic rings discussed hereinafter.Examples of cycloalkyl groups include but are not limited tocyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl, adamantanyl, bicyclo(2.2.1)heptanyl andcyclodecyl with cyclopropyl, cyclopentyl, cyclohexyl, adamantanyl, andbicyclo(2.2.1)heptanyl being particularly preferred. An “optionallysubstituted cycloalkyl” refers to a cycloalkyl having optionally one ormore substituents (for example 1 to 3 substituents, for example 1, 2, 3or 4 substituents), selected from those defined above for substitutedalkyl. When the suffix “ene” is used in conjunction with a cyclic group,hereinafter also referred to as “Cycloalkylene”, this is intended tomean the cyclic group as defined herein having two single bonds aspoints of attachment to other groups. Cycloalkylene groups of thisinvention preferably comprise the same number of carbon atoms as theircycloalkyl radical counterparts.

Where alkyl groups as defined are divalent, i.e., with two single bondsfor attachment to two other groups, they are termed “alkylene” groups.Non-limiting examples of alkylene groups includes methylene, ethylene,methylmethylene, trimethylene, propylene, tetramethylene, ethylethylene,1,2-dimethylethylene, pentamethylene and hexamethylene. Similarly, wherealkenyl groups as defined above and alkynyl groups as defined above,respectively, are divalent radicals having single bonds for attachmentto two other groups, they are termed “alkenylene” and “alkynylene”respectively.

Generally, alkylene groups of this invention preferably comprise thesame number of carbon atoms as their alkyl counterparts. Where analkylene or cycloalkylene biradical is present, connectivity to themolecular structure of which it forms part may be through a commoncarbon atom or different carbon atom, preferably a common carbon atom.To illustrate this applying the asterisk nomenclature of this invention,a C₃ alkylene group may be for example *—CH₂CH₂CH₂—*, *—CH(—CH₂CH₃)—*,or *—CH₂CH(—CH₃)—*. Likewise a C₃ cycloalkylene group may be

Where a cycloalkylene group is present, this is preferably a C₃-C₆cycloalkylene group, more preferably a C₃ cycloalkylene (i.e.cyclopropylene group) wherein its connectivity to the structure of whichit forms part is through a common carbon atom. Cycloalkylene andalkylene biradicals in compounds of the invention may be, but preferablyare not, substituted.

The terms “heterocyclyl” or “heterocyclo” as used herein by itself or aspart of another group refer to non-aromatic, fully saturated orpartially unsaturated cyclic groups (for example, 3 to 13 membermonocyclic, 7 to 17 member bicyclic, or 10 to 20 member tricyclic ringsystems, or containing a total of 3 to 10 ring atoms) which have atleast one heteroatom in at least one carbon atom-containing ring. Eachring of the heterocyclic group containing a heteroatom may have 1, 2, 3or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/orsulfur atoms, where the nitrogen and sulfur heteroatoms may optionallybe oxidized and the nitrogen heteroatoms may optionally be quaternized.The heterocyclic group may be attached at any heteroatom or carbon atomof the ring or ring system, where valence allows. The rings ofmulti-ring heterocycles may be fused, bridged and/or joined through oneor more spiro atoms. An optionally substituted heterocyclic refers to aheterocyclic having optionally one or more substituents (for example 1to 4 substituents, or for example 1, 2, 3 or 4), selected from thosedefined for substituted aryl.

Exemplary heterocyclic groups include piperidinyl, azetidinyl,imidazolinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl,isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidyl,succinimidyl, 3H-indolyl, isoindolinyl, chromenyl, isochromanyl,xanthenyl, 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl,pyrrolidinyl, 4H-quinolizinyl, 4aH-carbazolyl, 2-oxopiperazinyl,piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, pyranyl,dihydro-2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, phthalazinyl,oxetanyl, thietanyl, 3-dioxolanyl, 1,3-dioxanyl, 2,5-dioximidazolidinyl,2,2,4-piperidonyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl,indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrehydrothienyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, thiomorpholinyl,thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolanyl,1,4-oxathianyl, 1,4-dithianyl, 1,3,5-trioxanyl, 6H-1,2,5-thiadiazinyl,2H-1,5,2-dithiazinyl, 2H-oxocinyl, 1H-pyrrolizinyl,tetrahydro-1,1-dioxothienyl, N-formylpiperazinyl, and morpholinyl.

The term “aryl” as used herein refers to a polyunsaturated, aromatichydrocarbyl group having a single ring (i.e. phenyl) or multiplearomatic rings fused together (e.g. naphthalene or anthracene) or linkedcovalently, typically containing 6 to 10 atoms; wherein at least onering is aromatic. The aromatic ring may optionally include one to threeadditional rings (either cycloalkyl, heterocyclyl, or heteroaryl) fusedthereto. Aryl is also intended to include the partially hydrogenatedderivatives of the carbocyclic systems enumerated herein. Non-limitingexamples of aryl comprise phenyl, biphenylyl, biphenylenyl, 5- or6-tetralinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-azulenyl, 1- or2-naphthyl, 1-, 2-, or 3-indenyl, 1-, 2-, or 9-anthryl, 1-2-, 3-, 4-, or5-acenaphtylenyl, 3-, 4-, or 5-acenaphtenyl, 1-, 2-, 3-, 4-, or10-phenanthryl, 1- or 2-pentalenyl, 1,2-, 3-, or 4-fluorenyl, 4- or5-indanyl, 5-, 6-, 7-, or 8-tetrahydronaphthyl,1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl,dibenzo[a,d]cylcoheptenyl, and 1-, 2-, 3-, 4-, or 5-pyrenyl.

The aryl ring can optionally be substituted by one or more substituents.An “optionally substituted aryl” refers to an aryl having optionally oneor more substituents (for example 1 to 5 substituents, for example 1, 2,3 or 4) at any available point of attachment. Non-limiting examples ofsuch substituents are selected from halogen, hydroxyl, oxo, nitro,amino, hydrazine, aminocarbonyl, azido, cyano, alkyl, cycloalkyl,alkenyl, alkynyl, cycloalkylalkyl, alkylamino, alkoxy, —SO₂—NH₂, aryl,heteroaryl, aralkyl, haloalkyl, haloalkoxy, alkoxycarbonyl,alkylaminocarbonyl, heteroarylalkyl, alkylsulfonamide, heterocyclyl,alkylcarbonylaminoalkyl, aryloxy, alkylcarbonyl, acyl, arylcarbonyl,aminocarbonyl, alkylsulfoxide, —SO₂R^(a), alkylthio, carboxyl, and thelike, wherein R^(a) is alkyl or cycloalkyl.

Where a carbon atom in an aryl group is replaced with a heteroatom, theresultant ring is referred to herein as a heteroaryl ring.

The term “heteroaryl” as used herein by itself or as part of anothergroup refers but is not limited to 5 to 12 carbon-atom aromatic rings orring systems containing 1 to 3 rings which are fused together or linkedcovalently, typically containing 5 to 8 atoms; at least one of which isaromatic in which one or more carbon atoms in one or more of these ringscan be replaced by oxygen, nitrogen or sulfur atoms where the nitrogenand sulfur heteroatoms may optionally be oxidized and the nitrogenheteroatoms may optionally be quaternized. Such rings may be fused to anaryl, cycloalkyl, heteroaryl or heterocyclyl ring. Non-limiting examplesof such heteroaryl, include: pyrrolyl, furanyl, thiophenyl, pyrazolyl,imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl,oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl,pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl,thiazinyl, triazinyl, imidazo[2,1-b][1,3]thiazolyl,thieno[3,2-b]furanyl, thieno[3,2-b]thiophenyl,thieno[2,3-d][1,3]thiazolyl, thieno[2,3-d]imidazolyl,tetrazolo[1,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl,benzofuranyl, benzopyranyl, 1(4H)-benzopyranyl, 1(2H)-benzopyranyl,3,4-dihydro-1(2H)-benzopyranyl, 3,4-dihydro-1(2H)-benzopyranyl,isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl,benzimidazolyl, 1,3-benzoxazolyl, 1,2-benzisoxazolyl,2,1-benzisoxazolyl, 1,3-benzothiazolyl, 1,2-benzoisothiazolyl,2,1-benzoisothiazolyl, benzotriazolyl, 1,2,3-benzoxadiazolyl,2,1,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl,thienopyridinyl, purinyl, imidazo[1,2-a]pyridinyl,6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl,6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 1,3-benzodioxolyl,quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl,7-azaindolyl, 6-azaindolyl, 5-azaindolyl, 4-azaindolyl.

The term “pyrrolyl” (also called azolyl) as used herein includespyrrol-1-yl, pyrrol-2-yl and pyrrol-3-yl.

The term “furanyl” (also called “furyl”) as used herein includesfuran-2-yl and furan-3-yl (also called furan-2-yl and furan-3-yl). Theterm “thiophenyl” (also called “thienyl”) as used herein includesthiophen-2-yl and thiophen-3-yl (also called thien-2-yl and thien-3-yl).

The term “pyrazolyl” (also called 1H-pyrazolyl and 1,2-diazolyl) as usedherein includes pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl andpyrazol-5-yl.

The term “imidazolyl” as used herein includes imidazol-1-yl,imidazol-2-yl, imidazol-4-yl and imidazol-5-yl.

The term “oxazolyl” (also called 1,3-oxazolyl) as used herein includesoxazol-2-yl; oxazol-4-yl and oxazol-5-yl.

The term “isoxazolyl” (also called 1,2-oxazolyl), as used hereinincludes isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl. The term“thiazolyl” (also called 1,3-thiazolyl), as used herein includesthiazol-2-yl, thiazol-4-yl and thiazol-5-yl (also called 2-thiazolyl,4-thiazolyl and 5-thiazolyl).

The term “isothiazolyl” (also called 1,2-thiazolyl) as used hereinincludes isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl.

The term “triazolyl” as used herein includes 1H-triazolyl and4H-1,2,4-triazolyl, “1H-triazolyl” includes 1H-1,2,3-triazol-1-yl,1H-1,2,3-triazol-4-yl, 1H-1,2,3-triazol-5-yl, 1H-1,2,4-triazol-1-yl,1H-1,2,4-triazol-3-yl and 1H-1,2,4-triazol-5-yl. “4H-1,2,4-triazolyl”includes 4H-1,2,4-triazol-4-yl, and 4H-1,2,4-triazol-3-yl.

The term “oxadiazolyl” as used herein includes 1,2,3-oxadiazol-4-yl,1,2,3-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl,1,2,5-oxadiazol-3-yl and 1,3,4-oxadiazol-2-yl.

The term “thiadiazolyl” as used herein includes 1,2,3-thiadiazol-4-yl,1,2,3-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl,1,2,5-thiadiazol-3-yl (also called furazan-3-yl) and1,3,4-thiadiazol-2-yl.

The term “tetrazolyl” as used herein includes 1H-tetrazol-1-yl,1H-tetrazol-5-yl, 2H-tetrazol-2-yl, and 2H-tetrazol-5-yl.

The term “oxatriazolyl” as used herein includes 1,2,3,4-oxatriazol-5-yland 1,2,3,5-oxatriazol-4-yl.

The term “thiatriazolyl” as used herein includes1,2,3,4-thiatriazol-5-yl and 1,2,3,5-thiatriazol-4-yl.

The term “pyridinyl” (also called “pyridyl”) as used herein includespyridin-2-yl, pyridin-3-yl and pyridin-4-yl (also called 2-pyridyl,3-pyridyl and 4-pyridyl).

The term “pyrimidyl” as used herein includes pyrimid-2-yl, pyrimid-4-yl,pyrimid-5-yl and pyrimid-6-yl.

The term “pyrazinyl” as used herein includes pyrazin-2-yl andpyrazin-3-yl. The term “pyridazinyl as used herein includespyridazin-3-yl and pyridazin-4-yl.

The term “oxazinyl” (also called “1,4-oxazinyl”) as used herein includes1,4-oxazin-4-yl and 1,4-oxazin-5-yl.

The term “dioxinyl” (also called “1,4-dioxinyl”) as used herein includes1,4-dioxin-2-yl and 1,4-dioxin-3-yl.

The term “thiazinyl” (also called “1,4-thiazinyl”) as used hereinincludes 1,4-thiazin-2-yl, 1,4-thiazin-3-yl, 1,4-thiazin-4-yl,1,4-thiazin-5-yl and 1,4-thiazin-6-yl.

The term “triazinyl” as used herein includes 1,3,5-triazin-2-yl,1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl,1,2,3-triazin-4-yl and 1,2,3-triazin-5-yl.

The term “imidazo[2,1-b][1,3]thiazolyl” as used herein includesimidazo[2,1-b][1,3]thiazoi-2-yl, imidazo[2,1-b][1,3]thiazol-3-yl,imidazo[2,1-b][1,3]thiazol-5-yl and imidazo[2,1-b][1,3]thiazol-6-yl.

The term “thieno[3,2-b]furanyl” as used herein includesthieno[3,2-b]furan-2-yl, thieno[3,2-b]furan-3-yl,thieno[3,2-b]furan-4-yl, and thieno[3,2-b]furan-5-yl.

The term “thieno[3,2-b]thiophenyl” as used herein includesthieno[3,2-b]thien-2-yl, thieno[3,2-b]thien-3-yl,thieno[3,2-b]thien-5-yl and thieno[3,2-b]thien-6-yl.

The term “thieno[2,3-d][1,3]thiazolyl” as used herein includesthieno[2,3-d][1,3]thiazol-2-yl, thieno[2,3-d][1,3]thiazol-5-yl andthieno[2,3-d][1,3]thiazol-6-yl.

The term “thieno[2,3-d]imidazolyl” as used herein includesthieno[2,3-d]imidazol-2-yl, thieno[2,3-d]imidazol-4-yl andthieno[2,3-d]imidazol-5-yl.

The term “tetrazolo[1,5-a]pyridinyl” as used herein includestetrazolo[1,5-a]pyridine-5-yl, tetrazolo[1,5-a]pyridine-6-yl,tetrazolo[1,5-a]pyridine-7-yl, and tetrazolo[1,5-a]pyridine-8-yl.

The term “indolyl” as used herein includes indol-1-yl, indol-2-yl,indol-3-yl, -indol-4-yl, indol-5-yl, indol-6-yl and indol-7-yl.

The term “indolizinyl” as used herein includes indolizin-1-yl,indolizin-2-yl, indolizin-3-yl, indolizin-5-yl, indolizin-6-yl,indolizin-7-yl, and indolizin-8-yl.

The term “isoindolyl” as used herein includes isoindol-1-yl,isoindol-2-yl, isoindol-3-yl, isoindol-4-yl, isoindol-5-yl,isoindol-6-yl and isoindol-7-yl.

The term “benzofuranyl” (also called benzo[b]furanyl) as used hereinincludes benzofuran-2-yl, benzofuran-3-yl, benzofuran-4-yl,benzofuran-5-yl, benzofuran-6-yl and benzofuran-7-yl.

The term “isobenzofuranyl” (also called benzo[c]furanyl) as used hereinincludes isobenzofuran-1-yl, isobenzofuran-3-yl, isobenzofuran-4-yl,isobenzofuran-5-yl, isobenzofuran-6-yl and isobenzofuran-7-yl.

The term “benzothiophenyl” (also called benzo[b]thienyl) as used hereinincludes 2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl,4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl and-7-benzo[b]thiophenyl (also called benzothien-2-yl, benzothien-3-yl,benzothien-4-yl, benzothien-5-yl, benzothien-6-yl and benzothien-7-yl).

The term “isobenzothiophenyl” (also called benzo[c]thienyl) as usedherein includes isobenzothien-1-yl, isobenzothien-3-yl,isobenzothien-4-yl, isobenzothien-5-yl, isobenzothien-6-yl andisobenzothien-7-yl.

The term “indazolyl” (also called 1H-indazolyl or 2-azaindolyl) as usedherein includes 1H-indazol-1-yl, 1H-indazol-3-yl, 1H-indazol-4-yl,1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indazol-7-yl, 2H-indazol-2-yl,2H-indazol-3-yl, 2H-indazol-4-yl, 2H-indazol-5-yl, 2H-indazol-6-yl, and2H-indazol-7-yl.

The term “benzimidazolyl” as used herein includes benzimidazol-1-yl,benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl,benzimidazol-6-yl and benzimidazol-7-yl.

The term “1,3-benzoxazolyl” as used herein includes 1,3-benzoxazol-2-yl,1,3-benzoxazol-4-yl, 1,3-benzoxazol-5-yl, 1,3-benzoxazol-6-yl and1,3-benzoxazol-7-yl.

The term “1,2-benzisoxazolyl” as used herein includes1,2-benzisoxazol-3-yl, 1,2-benzisoxazol-4-yl, 1,2-benzisoxazol-5-yl,1,2-benzisoxazol-6-yl and 1,2-benzisoxazol-7-yl.

The term “2,1-benzisoxazolyl” as used herein includes2,1-benzisoxazol-3-yl, 2,1-benzisoxazol-4-yl, 2,1-benzisoxazol-5-yl,2,1-benzisoxazol-6-yl and 2,1-benzisoxazol-7-yl.

The term “1,3-benzothiazolyl” as used herein includes1,3-benzothiazol-2-yl, 1,3-benzothiazol-4-yl, 1,3-benzothiazol-5-yl,1,3-benzothiazol-6-yl and 1,3-benzothiazol-7-yl.

The term “1,2-benzoisothiazolyl” as used herein includes1,2-benzisothiazol-3-yl, 1,2-benzisothiazol-4-yl,1,2-benzisothiazol-5-yl, 1,2-benzisothiazol-6-yl and1,2-benzisothiazol-7-yl.

The term “2,1-benzoisothiazolyl” as used herein includes2,1-benzisothiazol-3-yl, 2,1-benzisothiazol-4-yl,2,1-benzisothiazol-5-yl, 2,1-benzisothiazol-6-yl and2,1-benzisothiazol-7-yl.

The term “benzotriazolyl” as used herein includes benzotriazol-1-yl,benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl andbenzotriazol-7-yl.

The term “1,2,3-benzoxadiazolyl” as used herein includes1,2,3-benzoxadiazol-4-yl, 1,2,3-benzoxadiazol-5-yl,1,2,3-benzoxadiazol-6-yl and 1,2,3-benzoxadiazol-7-yl.

The term “2,1,3-benzoxadiazolyl” as used herein includes2,1,3-benzoxadiazol-4-yl, 2,1,3-benzoxadiazol-5-yl,2,1,3-benzoxadiazol-6-yl and 2,1,3-benzoxadiazol-7-yl.

The term “1,2,3-benzothiadiazolyl” as used herein includes1,2,3-benzothiadiazol-4-yl, 1,2,3-benzothiadiazol-5-yl,1,2,3-benzothiadiazol-6-yl and 1,2,3-benzothiadiazol-7-yl.

The term “2,1,3-benzothiadiazolyl” as used herein includes2,1,3-benzothiadiazol-4-yl, 2,1,3-benzothiadiazol-5-yl,2,1,3-benzothiadiazol-6-yl and 2,1,3-benzothiadiazol-7-yl.

The term “thienopyridinyl” as used herein includesthieno[2,3-b]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2-c]pyridinyland thieno[3,2-b]pyridinyl.

The term “purinyl” as used herein includes purin-2-yl, purin-6-yl,purin-7-yl and purin-8-yl.

The term “imidazo[1,2-a]pyridinyl”, as used herein includesimidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyridin-3-yl,imidazo[1,2-a]pyridin-4-yl, imidazo[1,2-a]pyridin-5-yl,imidazo[1,2-a]pyridin-6-yl and imidazo[1,2-a]pyridin-7-yl.

The term “1,3-benzodioxolyl”, as used herein includes1,3-benzodioxol-4-yl, 1,3-benzodioxol-5-yl, 1,3-benzodioxol-6-yl, and1,3-benzodioxol-7-yl.

The term “quinolinyl” as used herein includes quinolin-2-yl,quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl,quinolin-7-yl and quinolin-8-yl.

The term “isoquinolinyl” as used herein includes isoquinolin-1-yl,isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl,isoquinolin-7-yl and isoquinolin-8-yl.

The term “cinnolinyl” as used herein includes cinnolin-3-yl,cinnolin-4-yl, cinnolin-5-yl, cinnolin-6-yl, cinnolin-7-yl andcinnolin-8-yl.

The term “quinazolinyl” as used herein includes quinazolin-2-yl,quiriazolin-4-yl, quinazolin-5-yl, quinazolin-6-yl, quinazolin-7-yl andquinazolin-8-yl.

The term “quinoxalinyl” as used herein includes quinoxalin-2-yl,quinoxalin-5-yl, and quinoxalin-6-yl.

The term “7-azaindolyl” as used herein refers to1H-Pyrrolo[2,3-b]pyridinyl and includes 7-azaindol-1-yl,7-azaindol-2-yl, 7-azaindol-3-yl, 7-azaindol-4-yl, 7-azaindol-5-yl,7-azaindol-6-yl.

The term “6-azaindolyl” as used herein refers to1H-Pyrrolo[2,3-c]pyridinyl and includes 6-azaindol-1-yl,6-azaindol-2-yl, 6-azaindol-3-yl, 6-azaindol-4-yl, 6-azaindol-5-yl,6-azaindol-7-yl.

The term “5-azaindolyl” as used herein refers to1H-Pyrrolo[3,2-c]pyridinyl and includes 5-azaindol-1-yl,5-azaindol-2-yl, 5-azaindol-3-yl, 5-azaindol-4-yl, 5-azaindol-6-yl,5-azaindol-7-yl.

The term “4-azaindolyl” as used herein refers to1H-Pyrrolo[3,2-b]pyridinyl and includes 4-azaindol-1-yl,4-azaindol-2-yl, 4-azaindol-3-yl, 4-azaindol-5-yl, 4-azaindol-6-yl,4-azaindol-7-yl.

For example, non-limiting examples of heteroaryl can be 2- or 3-furyl,2- or 3-thienyl, 1-,2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-,3-, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-oxazolyl, 3-,4- or 5-isothiazolyl, 2-, 4- or 5-thiazolyl, 1,2,3-triazol-1-, -4- or-5-yl, 1,2,4-triazol-1-, -3-, -4- or -5-yl, 1H-tetrazol-1-, or -5-yl,2H-tetrazol-2-, or -5-yl, 1,2,3-oxadiazol-4- or -5-yl,1,2,4-oxadiazol-3- or -5-yl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,3-thiadiazol-4- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl,1,2,5-thiadiazol-3- or -4-yl, 1,3,4-thiadiazolyl, 1- or 5-tetrazolyl,2-, 3- or 4-pyridyl, 3- or 4-pyridazinyl, 2-, 4-, 5- or 6-pyrimidyl, 2-,3-, 4-, 5-6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 4-azaindol-1-,2-, 3-, 5-, or 7-yl, 5-azaindol-1-, or 2-, 3-, 4-, 6-, or 7-yl,6-azaindol-1,2-, 3-, 4-, 5-, or 7-yl, 7-azaindol-1-, 2-, 3-, 4,5-, or6-yl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 1-, 3-, 4- or 5-isobenzofuryl,2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 3-, 4- or 5-isobenzothienyl,1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2- or 3-pyrazinyl, 1,4-oxazin-2- or-3-yl, 1,4-dioxin-2- or -3-yl, 1,4-thiazin-2- or -3-yl, 1,2,3-triazinyl,1,2,4-triazinyl, 1,3,5-triazin-2-, -4- or -6-yl, thieno[2,3-b]furan-2-,-3-, -4-, or -5-yl, benzimidazol-1-yl, -2-yl, -4-yl, -5-yl, -6-yl, or-7-yl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 3-, 4-, 5-, 6- or7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or7-benzisothiazolyl, 1,3-benzothiazol-2-yl, -4-yl, -5-yl, -6-yl or -7-yl,1,3-benzodioxol-4-yl, -5-yl, -6-yl, or -7-yl, benzotriazol-1-yl, -4-yl,-5-yl, -6-yl or -7-yl1-, 2-thianthrenyl, 3-, 4- or 5-isobenzofuranyl,1-, 2-, 3-, -4- or 9-xanthenyl, 1-, 2-, 3- or 4-phenoxathiinyl, 2-,3-pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-indolizinyl, 2-, 3-, 4- or5-isoindolyl, 1H-indazol-1-yl, 3-yl, -4-yl, -5-yl, -6-yl, or -7-yl,2H-indazol-2-yl, 3-yl, -4-yl, -5-yl, -6-yl, or -7-yl,imidazo[2,1-b][1,3]thiazoi-2-yl, imidazo[2,1-b][1,3]thiazol-3-yl,imidazo[2,1-b][1,3]thiazol-5-yl or imidazo[2,1-b][1,3]thiazol-6-yl,imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyridin-3-yl,imidazo[1,2-a]pyridin-4-yl, imidazo[1,2-a]pyridin-5-yl,imidazo[1,2-a]pyridin-6-yl or imidazo[1,2-a]pyridin-7-yl,tetrazolo[1,5-a]pyridine-5-yl, tetrazolo[1,5-a]pyridine-6-yl,tetrazolo[1,5-a]pyridine-7-yl, or tetrazolo[1,5-a]pyridine-8-yl, 2-, 6-,7- or 8-purinyl, 4-, 5- or 6-phthalazinyl, 2-, 3- or 4-naphthyridinyl,2-, 5- or 6-quinoxalinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 1-, 2-,3- or 4-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl(quinolyl),2-, 4-, 5-, 6-, 7- or 8-quinazolyl, 1-, 3-, 4-, 5-, 6-, 7- or8-isoquinolinyl(isoquinolyl), 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-,4-, 6- or 7-pteridinyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-,5-, 6-, 7-, 8- or 9-carbolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or10-phenanthridinyl, 1-, 2-, 3- or 4-acridinyl, 1-, 2-, 3-, 4-, 5-, 6-,7-, 8- or 9-perimidinyl, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or10-(1,7)phenanthrolinyl, 1- or 2-phenazinyl, 1-, 2-, 3-, 4-, or10-phenothiazinyl, 3- or 4-furazanyl, 1-, 2-, 3-, 4-, or10-phenoxazinyl, or additionally substituted derivatives thereof.

An “optionally substituted heteroaryl” refers to a heteroaryl havingoptionally one or more substituents (for example 1 to 4 substituents,for example 1, 2, 3 or 4), selected from those defined above forsubstituted aryl.

The term “oxo” as used herein refers to the group ═O.

The term “alkoxy” or “alkyloxy” as used herein refers to a radicalhaving the Formula —OR^(b) wherein R^(b) is alkyl. Preferably, alkoxy isC₁-C₁₀ alkoxy, C₁-C₆ alkoxy, or C₁-C₄ alkoxy. Non-limiting examples ofsuitable alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy. Where theoxygen atom in an alkoxy group is substituted with sulfur, the resultantradical is referred to as thioalkoxy. “Haloalkoxy” is an alkoxy groupwherein one or more hydrogen atoms in the alkyl group are substitutedwith halogen. Non-limiting examples of suitable haloalkoxy includefluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy,1,1,2,2-tetrafluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy,2,2-difluoroethoxy, 2,2,2-trichloroethoxy; trichloromethoxy,2-bromoethoxy, pentafluoroethyl, 3,3,3-trichloropropoxy,4,4,4-trichlorobutoxy.

The term “aryloxy” as used herein denotes a group —O-aryl, wherein arylis as defined above.

The term “arylcarbonyl” or “aroyl” as used herein denotes a group—C(O)-aryl, wherein aryl is as defined above.

The term “cycloalkylalkyl” by itself or as part of another substituentrefers to a group having one of the aforementioned cycloalkyl groupsattached to one of the aforementioned alkyl chains. Examples of suchcycloalkylalkyl radicals include cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl, cyclohexylmethyl, 1-cyclopentylethyl,1-cyclohexylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl,cyclobutylpropyl, cyclopentylpropyl, 3-cyclopentylbutyl, cyclohexylbutyland the like.

The term “heterocyclyl-alkyl” by itself or as part of anothersubstituents refers to a group having one of the aforementionedheterocyclyl group attached to one of the aforementioned alkyl group,i.e., to a group —R^(d)—R^(c) wherein R^(d) is alkylene or alkylenesubstituted by alkyl group and R^(c) is a heterocyclyl group.

The term “carboxy” or “carboxyl” or “hydroxycarbonyl” by itself or aspart of another substituent refers to the group —CO₂H. Thus, acarboxyalkyl is an alkyl group as defined above having at least onesubstituent that is —CO₂H.

The term “alkoxycarbonyl” by itself or as part of another substituentrefers to a carboxy group linked to an alkyl radical i.e. to form—C(═O)OR^(e), wherein R^(e) is as defined above for alkyl.

The term “alkylcarbonyloxy” by itself or as part of another substituentrefers to a —O—C(═O)R^(e) wherein R^(e) is as defined above for alkyl.

The term “alkylcarbonylamino” by itself or as part of anothersubstituent refers to an group of Formula —NH(C═O)R or —NR′(C═O)R,wherein R and R′ are each independently alkyl or substituted alkyl.

The term “thiocarbonyl” by itself or as part of another substituentrefers to the group —C(═S)—.

The term “alkoxy” by itself or as part of another substituent refers toa group consisting of an oxygen atom attached to one optionallysubstituted straight or branched alkyl group, cycloalkyl group, aralkyl,or cycloalkylalkyl group. Non-limiting examples of suitable alkoxy groupinclude methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy,sec-butoxy, tert-butoxy, hexanoxy, and the like.

The term “halo” or “halogen” as a group or part of a group is genericfor fluoro, chloro, bromo, or iodo.

The term “haloalkyl” alone or in combination, refers to an alkyl radicalhaving the meaning as defined above wherein one or more hydrogens arereplaced with a halogen as defined above. Non-limiting examples of suchhaloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl,difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and the like.

The term “haloaryl” alone or in combination, refers to an aryl radicalhaving the meaning as defined above wherein one or more hydrogens arereplaced with a halogen as defined above.

The term “haloalkoxy” alone or in combination refers to a group ofFormula —O-alkyl wherein the alkyl group is substituted by 1, 2, or 3halogen atoms. For example, “haloalkoxy” includes —OCF₃, —OCHF₂, —OCH₂F,—O—CF₂—CF₃, —O—CH₂—CF₃, —O—CH₂—CHF₂, and —O—CH₂—CH₂F.

Whenever the term “substituted” is used in the present invention, it ismeant to indicate that one or more hydrogens on the atom indicated inthe expression using “substituted” is replaced with a selection from theindicated group, provided that the indicated atom's normal valency isnot exceeded, and that the substitution results in a chemically stablecompound, i.e. a compound that is sufficiently robust to surviveisolation to a useful degree of purity from a reaction mixture, andformulation into a therapeutic agent.

Where groups may be optionally substituted, such groups may besubstituted with once or more, and preferably once, twice or thrice.Substituents may be selected from, for example, the group comprisinghalogen, hydroxyl, oxo, nitro, amido, carboxy, amino, cyano haloalkoxy,and haloalkyl.

As used herein the terms such as “alkyl, aryl, or cycloalkyl, each beingoptionally substituted with” or “alkyl, aryl, or cycloalkyl, optionallysubstituted with” refers to optionally substituted alkyl, optionallysubstituted aryl and optionally substituted cycloalkyl.

As described herein, some of the compounds of the invention may containone or more asymmetric carbon atoms that serve as a chiral center, whichmay lead to different optical forms (e.g. enantiomers ordiastereoisomers). The invention comprises all such optical forms in allpossible configurations, as well as mixtures thereof.

More generally, from the above, it will be clear to the skilled personthat the compounds of the invention may exist in the form of differentisomers and/or tautomers, including but not limited to geometricalisomers, conformational isomers, E/Z-isomers, stereochemical isomers(i.e. enantiomers and diastereoisomers) and isomers that correspond tothe presence of the same substituents on different positions of therings present in the compounds of the invention. All such possibleisomers, tautomers and mixtures thereof are included within the scope ofthe invention.

Whenever used in the present invention the term “compounds of theinvention” or a similar term is meant to include the compounds ofgeneral Formula I and any subgroup thereof. This term also refers to thecompounds as depicted in Tables 1 to 11, their derivatives, N-oxides,salts, solvates, hydrates, stereoisomeric forms, racemic mixtures,tautomeric forms, optical isomers, analogues, pro-drugs, esters, andmetabolites, as well as their quaternized nitrogen analogues. TheN-oxide forms of said compounds are meant to comprise compounds whereinone or several nitrogen atoms are oxidized to the so-called N-oxide.

As used in the specification and the appended claims, the singular forms“a”, “an”, and “the” include plural referents unless the context clearlydictates otherwise. By way of example, “a compound” means one compoundor more than one compound.

The terms described above and others used in the specification are wellunderstood to those in the art.

In a further embodiment, the present invention provides compounds offormula I wherein;

R¹ is hydrogen, or C₁₋₄alkyl; in particular methyl;Ar is as defined hereinbefore, andY is an aryl or heteroaryl substituted with a substituent selected fromthe group consisting of —C(═O)—OR²¹; —C(═O)—SR²²; —C(═O)—NR³R⁴; —NR⁵R⁶;—O—C₁₋₆alkyl; —C₁₋₆alkyl; or —C₂₋₈alkenyl;

-   -   wherein said —O—C₁₋₆alkyl, —C₁₋₆alkyl, or —C₂₋₈alkenyl are each        independently substituted with a substituent selected from the        group consisting of C(═O)—OR²¹; —C(═O)—SR²²; —C(═O)—NR³R⁴; Het¹;        —O-Het²; and —S-Het³;

R³ is selected from the group consisting of hydrogen; C₁₋₂₀alkyloptionally substituted with 1, 2 or 3 substituents each independentlyselected from the group consisting of —C(═O)—OR²¹; —C(═O)—SR²²;—C(═O)—NR⁷R⁸; Het¹; —O-Het²; —S-Het³; C₁₋₆alkyl-S— and C₁₋₆alkyl-O—; inparticular R³ is hydrogen;

R⁴ is selected from the group consisting of C₁₋₂₀alkyl substituted with1, 2 or 3 substituents each independently selected from the groupconsisting of —C(═O)—OR²¹; —C(═O)—SR²²; —C(═O)—NR⁷R⁸; Het¹; —O-Het²;—S-Het³; C₁₋₆alkyl-S— and C₁₋₆alkyl-O—; in particular R⁴ is selectedfrom the group consisting of C₁₋₂₀alkyl substituted with 1, 2 or 3substituents each independently selected from the group consisting of—C(═O)—OR²¹; —C(═O)—SR²²; —C(═O)—NR⁷R⁸; Het¹; —O-Het²; and —S-Het³; or

R³ and R⁴ together with the nitrogen atom to which they are attachedform a heterocycle substituted with one substituent selected from thegroup consisting of —C(═O)—OR²¹; —C(═O)—SR²²; —C(═O)—NR⁹R¹⁰; Het¹;—O-Het²; —S-Het³; or C₁₋₆alkyl wherein said C₁₋₆alkyl is substitutedwith 1, 2, or 3 substituents each independently selected from the groupconsisting of —C(═O)—OR²¹; —C(═O)—SR²²; —C(═O)—NR⁹R¹⁰; Het¹; —O-Het²;and —S-Het³; in particular R³ and R⁴ together with the nitrogen atom towhich they are attached form a heterocycle substituted with onesubstituent selected from the group consisting of —C(═O)—OR²¹;—C(═O)—SR²²; —C(═O)—NR⁹R¹⁰; Het¹; or C₁₋₆alkyl wherein said C₁₋₆alkyl issubstituted with 1, 2, or 3 substituents each independently selectedfrom the group consisting of —C(═O)—OR²¹; —C(═O)—NR⁹R¹⁰; Het¹; —O-Het²;and —S-Het³; more in particular R³ and R⁴ together with the nitrogenatom to which they are attached form a heterocycle substituted with onesubstituent selected from the group consisting of —C(═O)—OR²¹;—C(═O)—SR²²; —C(═O)—NR⁹R¹⁰; Het¹; —O-Het²; and —S-Het³;

R⁵ or R⁶ are independently selected from the group consisting ofhydrogen; C₁₋₆alkyl; C₁₋₆alkyl-O—C₁₋₆alkyl-; C₁₋₆alkyl-S—C₁₋₆alkyl-;C₂₋₈alkenyl; C₁₋₆alkyl-C(═O)— or C₂₋₈alkenyl-C(═O)—; wherein at leastone of R⁵ or R⁶ is selected from C₁₋₆alkyl; C₁₋₆alkyl-O—C₁₋₆alkyl-;C₁₋₆alkyl-S—C₁₋₆alkyl-; or C₁₋₆alkyl-C(═O)—, and wherein each of saidC₁₋₆alkyl; C₁₋₆alkyl-O—C₁₋₆alkyl-; C₁₋₆alkyl-S—C₁₋₆alkyl-; orC₁₋₆alkyl-C(═O)— is substituted with 1, 2, or 3 substituents eachindependently selected from the group consisting of —C(═O)—OR²¹;—C(═O)—SR²²; Het¹; —O-Het²; and —S-Het³; in particular R⁵ or R⁶ areindependently selected from the group consisting of hydrogen; C₁₋₆alkyl;C₁₋₆alkyl-S—C₁₋₆alkyl-; or C₁₋₆alkyl-C(═O)—; wherein at least one of R⁵or R⁶ is selected from C₁₋₆alkyl; C₁₋₆alkyl-S—C₁₋₆alkyl-; orC₁₋₆alkyl-C(═O)—, and wherein each of said C₁₋₆alkyl;C₁₋₆alkyl-S—C₁₋₆alkyl-; or C₁₋₆alkyl-C(═O)— is substituted with 1, 2, or3 substituents each independently selected from the group consisting of—C(═O)—OR²¹; -Het¹; —O-Het²; and —S-Het³; more in particular R⁵ or R⁶are independently selected from the group consisting of hydrogen;C₁₋₆alkyl; or C₁₋₆alkyl-C(═O)—; wherein at least one of R⁵ or R⁶ isselected from C₁₋₆alkyl; or C₁₋₆alkyl-C(═O)—, and wherein each of saidC₁₋₆alkyl; or C₁₋₆alkyl-C(═O)— is substituted with 1, 2, or 3substituents each independently selected from the group consisting of—C(═O)—OR²¹; -Het¹; —O-Het²; and —S-Het³; even more in particular R⁵ orR⁶ are independently selected from the group consisting of hydrogen; orC₁₋₆alkyl; wherein at least one of R⁵ or R⁶ is C₁₋₆alkyl substitutedwith 1, 2, or 3 substituents each independently selected from the groupconsisting of -Het¹; —O-Het²; and —S-Het³;

R⁷ or R⁸ are independently selected from the group consisting ofhydrogen; or C₁₋₆alkyl substituted with 1, 2, or 3 substituents eachindependently selected from the group consisting of aryl, heteroaryl,C₃₋₆cycloalkenyl, —C(═O)—OR²¹; and —C(═O)—NH₂; in particular R⁷ or R⁸are independently selected from the group consisting of hydrogen; orC₁₋₆alkyl substituted with 1, 2, or 3 substituents each independentlyselected from the group consisting of —C(═O)—OR²¹; and —C(═O)—NH₂; morein particular R⁷ or R⁸ are independently selected from the groupconsisting of hydrogen; or C₁₋₆alkyl substituted with —C(═O)—OR²¹;

R⁹ or R¹⁰ are independently selected from the group consisting ofhydrogen; or C₁₋₆alkyl substituted with 1, 2, or 3, —C(═O)—OR²¹substituents;

R¹³ or R¹⁴ are independently selected from the group consisting ofhydrogen; C₁₋₆alkyl; C₁₋₆alkyl; C₁₋₆alkyl-O—C₁₋₆alkyl-;C₁₋₆alkyl-S—C₁₋₆alkyl-; or C₁₋₆alkyl-C(═O)— and wherein each of saidC₁₋₆alkyl; C₁₋₆alkyl-O—C₁₋₆alkyl-; C₁₋₆alkyl-S—C₁₋₆alkyl-; orC₁₋₆alkyl-C(═O)— is substituted with 1, 2, or 3 substituents eachindependently selected from the group consisting of —C(═O)—OR²¹;—C(═O)—SR²²; Het¹; —O-Het²; and —S-Het³; in particular R¹³ and R¹⁴represent hydrogen;

R²¹ is selected from the group consisting of C₁₋₂₀alkyl; C₁₋₂₀alkenyl;optionally substituted C₃₋₁₅cycloalkyl; optionally substitutedheterocyclyl; and optionally substituted aryl;

-   -   wherein said C₁₋₂₀alkyl is optionally substituted with 1, 2, 3        or more substituents selected from the group consisting of halo,        cyano, hydroxy, aryl-O—, aryl-S—, aryl-S(═O)₂—, aryl-C(═O),        —C(═O)—NR¹³R¹⁴, —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl-O—, C₁₋₆alkyl-S—,        aryl, heteroaryl, heterocyclyl and C₃₋₁₅cycloalkyl or from the        formula:

R²¹ taken together with the oxycarbonyl and phenyl to which it isattached forms a cyclic ester consisting of

wherein q is an integer from 1 to 6;

R²² is C₁₋₂₀alkyl optionally substituted with 1, 2, 3 or more halosubstituents;

Het¹, Het² or Het³ are independently selected from the group comprising;

Another group of interesting compounds according to the presentinvention are those compounds of formula (I) wherein one or more of thefollowing restrictions apply;

Ar represents pyridinyl, optionally substituted with halo; in particularAr represents pyridinyl substituted with fluoro; in an even furtherembodiment Ar represents pyridinyl substituted with fluoro; in an evenfurther embodiment Ar represents

wherein X is hydrogen or halo; in particular X is hydrogen or fluoro;more in particular X is fluoro;

R¹ represents hydrogen or C₁₋₄alkyl; in particular C₁₋₄alkyl; more inparticular methyl;

Y is an aryl or heteroaryl substituted with a substituent selected fromthe group consisting of —C(═O)—NR³R⁴; —NR⁵R⁶; —O—C₁₋₆alkyl; or—C₁₋₆alkyl;

-   -   wherein said —O—C₁₋₆alkyl or —C₁₋₆alkyl are each independently        substituted with a substituent selected from the group        consisting of —C(═O)—NR³R⁴, —O-Het² and S-Het³; with in a        particular embodiment said Het² or Het³ independently being        selected from

the group comprising

Y is an aryl or heteroaryl substituted with a substituent selected fromthe group consisting of —C(═O)—OR²¹; —C(═O)—SR²²; —C(═O)—NR³R⁴;—O—C₁₋₆alkyl; or —C₁₋₆alkyl;

-   -   wherein said —O—C₁₋₆alkyl or —C₁₋₆alkyl are each independently        substituted with a substituent selected from the group        consisting of —C(═O)—OR²¹, and Het¹; with in a particular        embodiment said;    -   R²¹ being selected from —C₁₋₆alkyl or aryl; more in particular        said R²¹ being selected from —C₁₋₆alkyl or phenyl; and    -   said Het¹ being selected from the group comprising

R³ is hydrogen;

R⁴ is —C₁₋₆alkyl substituted with a substituent selected from —O-Het² or—S-Het³;

R⁴ is —C₁₋₆alkyl substituted with a substituent selected from—C(═O)—OR²¹, —C(═O)—SR²², or Het¹; with in a particular embodiment saidR²¹ being a —C₁₋₆alkyl substituted with a substituent selected from—C(═O)—OR²¹, or Het¹; with in a more particular embodiment said R²¹being a —C₁₋₆alkyl ;

R⁵ or R⁶ are independently selected from the group consisting ofhydrogen; C₁₋₆alkyl; or C₁₋₆alkyl-S—C₁₋₆alkyl-; wherein at least one ofR⁵ or R⁶ is selected from the group consisting of C₁₋₆alkyl; orC₁₋₆alkyl-S—C₁₋₆alkyl-; and wherein each of said C₁₋₆alkyl; orC₁₋₆alkyl-S—C₁₋₆alkyl-; is substituted with a substituent selected fromthe group consisting of —C(═O)—OR²¹, Het¹ and —S-Het³; with in aparticular embodiment said;

-   -   R²¹ being selected from —C₁₋₆alkyl or aryl; more in particular        said R²¹ being a —C₁₋₆alkyl; and    -   said Het¹ or Het³ independently being selected from the group

comprising

R²¹ is selected from —C₁₋₆alkyl, aryl or optionally substitutedheteroaryl; more in particular said R²¹ being selected from —C₁₋₆alkyl,3,4-dihydro-1(2H)-benzopyranyl, 3,4-dihydro-1(2H)-benzopyranyl, orphenyl, wherein said 3,4-dihydro-1(2H)-benzopyranyl,3,4-dihydro-1(2H)-benzopyranyl, is substituted with oxo;

Aryl represents phenyl;

Heteroaryl represents 3,4-dihydro-1(2H)-benzopyranyl,3,4-dihydro-1(2H)-benzopyranyl, or indolyl; in particular indolyl;

Y is an aryl or heteroaryl substituted with a substituent selected fromthe group consisting of —C(═O)—OR²¹; —C(═O)—SR²²; —C(═O)—NR³R⁴;—O—C₁₋₆alkyl; or —C₁₋₆alkyl;

-   -   wherein said —O—C₁₋₆alkyl or —C₁₋₆alkyl are each independently        substituted with a substituent selected from the group        consisting of —C(═O)—OR²¹, and Het¹; with in a particular        embodiment said;        -   R²¹ being selected from —C₁₋₆alkyl or aryl; more in            particular said R²¹ being selected from —C₁₋₆alkyl or            phenyl;    -   said Het¹ being selected from the group comprising

and wherein said —C(═O)—OR²¹; —C(═O)—SR²²; —C(═O)—NR³R⁴; —O—C₁₋₆alkyl;or —C₁₋₆alkyl are at the meta or para position vis-à-vis the binding ofthe aryl or heteroaryl to the remainder of the molecule such asrepresented in in formulae IIa-XXIIIa, and IIb-XXIIIb below.

In a particular embodiment, the present invention provides compounds offormula I, wherein the Y substituent in its definitions, i.e. as asubstituent or as part of a substituent comprises at least one groupselected from C(═O)—OR²¹; —C(═O)—SR²²; Het¹; —O-Het²; and —S-Het³. In amore particular embodiment, the present invention provides the compoundsof formula I, wherein the further substituents to the Y substituent areat the meta or para position vis-à-vis the binding of said aryl orheteroaryl to the remainder of the molecule and/or as represented informulae IIa-XXIIIa, and IIb-XXIIIb below.

In an even further embodiment, the present invention provides compoundsof formula I, as defined in any one of the different embodimentsdescribed herein, with the proviso that when Y represents an aryl orheteroaryl substituted with a substituent selected from the —C(═O)—OR²¹;or —C(═O)—SR²²; and wherein said R²¹ or R²² represents an unsubstitutedC₁₋₂₀alkyl; said —C(═O)—OR²¹; or —C(═O)—SR²²; is at the meta or paraposition vis-à-vis the binding of said aryl or heteroaryl to theremainder of the molecule and as represented in formulae IIa, IIb, IIIaand IIIb below.

In a further embodiment, the present invention provides compounds offormula I, wherein one or more of the following restrictions apply;

Y is 2-oxo-2,3-dihydrobenzofuranyl or Y is a phenyl, indolyl orthiophenyl, said phenyl indolyl and thiophenyl being substituted with asubstituent selected from the group consisting of —C(═O)—OR²¹;—C(═O)—SR²²; —C(═O)—NR³R⁴; —NR⁵R⁶; —O—C₁₋₆alkyl; —C₁₋₆alkyl; or—C₂₋₈alkenyl

-   -   wherein said —O—C₁₋₆alkyl or —C₂₋₈alkenyl is substituted with a        substituent selected from the group consisting of C(═O)—OR²¹;        —C(═O)—SR²²; —C(═O)—NR³R⁴; Het¹; —O-Het²; and —S-Het³;

R⁵ or R⁶ are independently selected from the group consisting ofhydrogen; C₁₋₆alkyl; or C₁₋₆alkyl-S—C₁₋₆alkyl-; wherein at least one ofR⁵ or R⁶ is selected from the group consisting of C₁₋₆alkyl; orC₁₋₆alkyl-S—C₁₋₆alkyl-; and wherein each of said C₁₋₆alkyl; orC₁₋₆alkyl-S—C₁₋₆alkyl-; is substituted with a substituent selected fromthe group consisting of —C(═O)—OR²¹, Het¹ and —S-Het³;

R²¹ is selected from the group consisting of C₁₋₂₀alkyl; optionallysubstituted C₃₋₁₀cycloalkyl; optionally substituted aryl; and optionallysubstituted heterocyclyl; wherein said C₁₋₂₀alkyl is optionallysubstituted with a substituent selected from the group consisting ofhalo, cyano, hydroxy, —C(═O)—NR¹³R¹⁴, —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl-O—,C₁₋₆alkyl-S—, aryl, heteroaryl, heterocyclyl, and C₃₋₁₀cycloalkyl, orfrom the formula:

-   -   in particular R²¹ is selected from the group consisting of        C₁₋₂₀alkyl; optionally substituted C₃₋₁₀cycloalkyl; optionally        substituted aryl; and optionally substituted heterocyclyl;        wherein said C₁₋₂₀alkyl is substituted with a substituent        selected from the group consisting of halo, cyano, hydroxy,        —C(═O)—NR¹³R¹⁴, —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl-O—, C₁₋₆alkyl-S—,        aryl, heteroaryl, heterocyclyl, and C₃₋₁₀cycloalkyl, or from the        formula:

more in particular R²¹ is selected from the group consisting ofC₁₋₂₀alkyl; C₃₋₁₀cycloalkyl; and optionally substituted aryl; whereinsaid C₁₋₂₀alkyl is substituted with a substituent selected from thegroup consisting of halo, —O—C(═O)—C₁₋₆alkyl, or from the formula:

heterocyclyl as used herein is selected from the group consisting ofpiperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl,1,3-dioxanyl, 3-dioxolanyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyland hexahydrofuro[3,2-b]furanyl; in particular piperidinyl,1,3-dioxanyl, indolinyl, tetrahydropyranyl and tetrahydrofuranyl;

optionally substituted C₃₋₁₀cycloalkyl as used herein is selected fromthe group consisting of cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, adamantanyl,bicyclo(2.2.1)heptanyl and cyclodecyl with cyclopropyl, cyclopentyl,cyclohexyl, adamantanyl, and bicyclo(2.2.1)heptanyl being particularlypreferred; wherein said C₃₋₁₀cycloalkyl is optionally substituted with1, 2, 3, or more in particular 1, 2 or 3; more in particular 1 or 2;even more in particular 1 substituent selected from halogen, hydroxyl,oxo, nitro, amino, cyano, C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy, or—SO₂—NH₂,

optionally substituted heterocyclyl as used herein is selected from thegroup consisting of piperidinyl, pyrrolidinyl, morpholinyl,thiomorpholinyl, piperazinyl, 1,3-dioxanyl, 3-dioxolanyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolinyl,tetrahydropyranyl, tetrahydrofuranyl and hexahydrofuro[3,2-b]furanyl; inparticular piperidinyl, 1,3-dioxanyl, indolinyl, tetrahydropyranyl andtetrahydrofuranyl; wherein said heterocyclyl is optionally substitutedwith 1, 2, 3 or more; in particular 1 substituent selected from thegroup consisting of halogen, hydroxyl, oxo, nitro, amino, hydrazine,aminocarbonyl, azido, cyano, alkyl, cycloalkyl, alkenyl, alkynyl,cycloalkylalkyl, alkylamino, alkoxy, —SO₂—NH₂, aryl, heteroaryl,aralkyl, haloalkyl, haloalkoxy, alkoxycarbonyl, alkylaminocarbonyl,heteroarylalkyl, alkylsulfonamide, heterocyclyl,alkylcarbonylaminoalkyl, aryloxy, alkylcarbonyl, acyl, arylcarbonyl,aminocarbonyl, alkylsulfoxide, —SO₂R^(a), alkylthio, carboxyl, and thelike, wherein R^(a) is alkyl or cycloalkyl; preferably selected fromhalogen, hydroxyl, oxo, nitro, amino, cyano, C₁₋₄alkyl, C₃₋₆cycloalkyl,C₁₋₄alkoxy, or —SO₂—NH₂.

aryl as used herein is selected from the group consisting of phenyl,naphtyl, 1,4-dihydro naphtyl, or 1,2,3,4-tetrahydronaphtyl wherein saidaryl is optionally substituted with 1, 2, 3, 4 or 5 substituentsselected from halogen, nitro, C₁₋₄alkyl, C₁₋₄alkyloxy, or C₁₋₄alkylthio;in particular phenyl or 1,2,3,4-tetrahydronaphtyl wherein said aryl isoptionally substituted with 1, 2, 3, 4 or 5 substituents selected fromhalogen, oxo, nitro, C₁₋₄alkyl, C₁₋₄alkyloxy, or C₁₋₄alkylthio; more inparticular phenyl optionally substituted with 1, 2, 3, 4 or 5substituents selected from halogen, nitro, C₁₋₄alkyl, C₁₋₄alkyloxy, orC₁₋₄alkylthio;

heteroaryl as used herein is selected from the group consisting offuranyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, benzopyranyl,1(4H)-benzopyranyl, 1(2H)-benzopyranyl, 3,4-dihydro-1(2H)-benzopyranyl,and 2,3-dihydro-1(4H)-benzopyranyl wherein said heteroaryl is optionallysubstituted with 1, 2, 3, 4 or 5 substituents selected from halogen,oxo, nitro, C₁₋₄alkyl, C₁₋₄alkyloxy, or C₁₋₄alkylthio; in particularfuranyl, thiohenyl, pyridinyl, benzopyranyl, 1(2H)-benzopyranyl,3,4-dihydro-1(2H)-benzopyranyl, and 2,3-dihydro-1(4H)-benzopyranylwherein said heteroaryl is optionally substituted with 1, 2, 3, 4 or 5substituents selected from halogen, oxo, or C₁₋₄alkyl;

Y is 2-oxo-2,3-dihydrobenzofuranyl or Y is a phenyl, indolyl orthiophenyl, said phenyl indolyl and thiophenyl being substituted with asubstituent selected from the group consisting of —C(═O)—OR²¹;—C(═O)—SR²²; —C(═O)—NR³R⁴; —NR⁵R⁶; —O—C₁₋₆alkyl; —C₁₋₆alkyl; or—C₂₋₈alkenyl; said —C(═O)—OR²¹; —C(═O)—SR²²; —C(═O)—NR³R⁴; —NR⁵R⁶;—O—C₁₋₆alkyl; —C₁₋₆alkyl; or —C₂₋₈alkenyl being bound at the meta orpara position of Y, vis-à-vis the binding of Y to the remainder of themolecule; and wherein said —O—C₁₋₆alkyl or —C₂₋₈alkenyl is substitutedwith a substituent selected from the group consisting of C(═O)—OR²¹;—C(═O)—SR²²; —C(═O)—NR³R⁴; Het¹; —O-Het²; and —S-Het³;

with the proviso that when Y is a phenyl, indolyl or thiophenyl, saidphenyl indolyl and thiophenyl being substituted with —C(═O)—OR²¹; or—C(═O)—SR²²; and wherein said R²¹ or R²² represents an unsubstitutedC₁₋₂₀alkyl; said —C(═O)—OR²¹; or —C(═O)—SR²²; is at the meta or paraposition vis-à-vis the binding of said phenyl, indolyl or thiophenyl tothe remainder of the molecule and as represented in formulae IIa, IIb,IIIa and IIIb below.

An interesting group of compounds, are those compounds of the presentinvention presented by formula Ia

wherein;

R¹ is selected form the group comprising hydrogen, C₁₋₄alkyl orC₃₋₆cycloalkyl;

Ar is selected from the group comprising:

Wherein X is selected from the group comprising hydrogen or halo;

L is a direct bond, C₁₋₄alkyl, or —O—C₁₋₄alkyl;

T is —O—R²¹ or —NR³R⁴;

R³ is selected from the group consisting of hydrogen; C₁₋₂₀alkyloptionally substituted with 1, 2 or 3 substituents each independentlyselected from the group consisting of —C(═O)—OR²¹; —C(═O)—SR²²;—C(═O)—NR⁷R⁸; Het¹; —O-Het²; —S-Het³; C₁₋₆alkyl-S— and C₁₋₆alkyl-O—; inparticular R³ is hydrogen;

R⁴ is selected from the group consisting of C₁₋₂₀alkyl substituted with1, 2 or 3 substituents each independently selected from the groupconsisting of —C(═O)—OR²¹; —C(═O)—SR²²; —C(═O)—NR⁷R⁸; Het¹; —O-Het²;—S-Het³; C₁₋₆alkyl-S— and C₁₋₆alkyl-O—; more in particular R⁴ isselected from the group consisting of C₁₋₂₀alkyl substituted with 1, 2or 3 substituents each independently selected from the group of—C(═O)—OR²¹; —C(═O)—SR²²; —C(═O)—NR⁷R⁸; Het¹; —O-Het²; and —S-Het³; or;

R³ and R⁴ together with the nitrogen atom to which they are attachedform a heterocycle substituted with one substituent selected from thegroup consisting of —C(═O)—OR²¹; —C(═O)—SR²²; —C(═O)—NR⁹R¹⁰; Het¹;—O-Het²; —S-Het³; or C₁₋₆alkyl wherein said C₁₋₆alkyl is substitutedwith 1, 2, or 3 substituents each independently selected from the groupconsisting of —C(═O)—OR²¹; —C(═O)—SR²²; —C(═O)—NR⁹R¹⁰; Het¹; —O-Het²;and —S-Het³; in particular R³ and R⁴ together with the nitrogen atom towhich they are attached form a heterocycle substituted with onesubstituent selected from the group consisting of —C(═O)—OR²¹;—C(═O)—SR²²; —C(═O)—NR⁹R¹⁰; Het¹; or C₁₋₆alkyl wherein said C₁₋₆alkyl issubstituted with 1, 2, or 3 substituents each independently selectedfrom the group consisting of Het¹; —O-Het²; and —S-Het³;

R⁷ or R⁸ are independently selected from the group consisting ofhydrogen; or C₁₋₆alkyl substituted with 1, 2, or 3 substituents eachindependently selected from the group consisting of aryl, heteroaryl,C₃₋₆cycloalkenyl, —C(═O)—OR²¹; and —C(═O)—NH₂; in particular R⁷ or R⁸are independently selected from the group consisting of hydrogen; orC₁₋₆alkyl substituted with 1, 2, or 3 substituents each independentlyselected from the group consisting of —C(═O)—OR²¹; and —C(═O)—NH₂;

R⁹ or R¹⁰ are independently selected from the group consisting ofhydrogen; or C₁₋₆alkyl substituted with 1, 2, or 3, —C(═O)—OR²¹substituents;

R¹³ or R¹⁴ are independently selected from the group consisting ofhydrogen; C₁₋₆alkyl; C₁₋₆alkyl; C₁₋₆alkyl-O—C₁₋₆alkyl-;C₁₋₆alkyl-S—C₁₋₆alkyl-; or C₁₋₆alkyl-C(═O)— and wherein each of saidC₁₋₆alkyl; C₁₋₆alkyl-O—C₁₋₆alkyl-; C₁₋₆alkyl-S—C₁₋₆alkyl-; orC₁₋₆alkyl-C(═O)— is substituted with 1, 2, or 3 substituents eachindependently selected from the group consisting of —C(═O)—OR²¹;—C(═O)—SR²²; Het¹; —O-Het²; and —S-Het³;

R²¹ is selected from the group consisting of C₁₋₂₀alkyl; C₁₋₂₀alkenyl;C₁₋₂₀alkynyl; optionally substituted C₃₋₁₅cycloalkyl; optionallysubstituted heterocyclyl; and optionally substituted aryl;

-   -   wherein said C₁₋₂₀alkyl is optionally substituted with 1, 2, 3        or more substituents selected from the group consisting of halo,        cyano, hydroxy, aryl-O—, aryl-S—, aryl-S(═O)₂—, aryl-C(═O),        —C(═O)—NR¹³R¹⁴, —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl-O—, C₁₋₆alkyl-S—,        aryl, heteroaryl, heterocyclyl and C₃₋₁₅cycloalkyl or from the        formula:

R²¹ taken together with the oxycarbonyl and phenyl to which it isattached forms a cyclic ester consisting of

wherein q is an integer from 1 to 6;

R²² is C₁₋₂₀alkyl optionally substituted with 1, 2, 3 or more halosubstituents;

Het¹, Het² or Het³ are independently selected from the group comprising;

In a further embodiment the present invention provides those compoundsof formula (Ia) wherein one or more of the following restrictions apply;

Ar represents pyridinyl, optionally substituted with halo; in particularAr represents pyridinyl substituted with fluoro; in an even furtherembodiment Ar represents

wherein X is hydrogen or halo; in particular X is hydrogen or fluoro;more in particular X is hydrogen;

R¹ represents hydrogen or C₁₋₄alkyl; in particular C₁₋₄alkyl; more inparticular methyl;

R³ is hydrogen;

R⁴ is —C₁₋₆alkyl substituted with a substituent selected from —O-Het²,or —S-Het³; with in a particular embodiment said Het² or Het³ beingselected from the group consisting of

R⁴ is —C₁₋₆alkyl substituted with a substituent selected from—C(═O)—OR²¹, —C(═O)—SR²², —C(═O)—NR⁷R⁸, or Het¹; in particular—C₁₋₆alkyl substituted with a substituent selected from —C(═O)—OR²¹, orHet¹; with in a particular embodiment said R²¹ being a —C₁₋₆alkyl andsaid Het¹ being

or

R³ and R⁴ together with the nitrogen atom to which they are attachedform a heterocycle substituted with C₁₋₆alkyl wherein said C₁₋₆alkyl issubstituted with 1, 2, or 3 substituents each independently selectedfrom the group consisting of —C(═O)—OR²¹; and —C(═O)—NR⁹R¹⁰;

R²¹ is selected from the group consisting of C₁₋₂₀alkyl; optionallysubstituted C₃₋₁₀cycloalkyl; optionally substituted aryl; and optionallysubstituted heterocyclyl; wherein said C₁₋₂₀alkyl is optionallysubstituted with a substituent selected from the group consisting ofhalo, cyano, hydroxy, —C(═O)—NR¹³R¹⁴, —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl-O—,C₁₋₆alkyl-S—, aryl, heterocyclyl, and C₃₋₁₀cycloalkyl, or from theformula:

in particular R²¹ is selected from the group consisting of C₁₋₂₀alkyl;optionally substituted C₃₋₁₀cycloalkyl; optionally substituted aryl; andoptionally substituted heterocyclyl; wherein said C₁₋₂₀alkyl issubstituted with a substituent selected from the group consisting ofhalo, cyano, hydroxy, —C(═O)—NR¹³R¹⁴, —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl-O—,C₁₋₆alkyl-S—, aryl, heterocyclyl, and C₃₋₁₀cycloalkyl, or from theformula:

-   -   more in particular R²¹ is selected from the group consisting of        C₁₋₂₀alkyl; optionally substituted C₃₋₁₀cycloalkyl; optionally        substituted aryl; and optionally substituted heterocyclyl;        wherein said C₁₋₂₀alkyl is substituted with a substituent        selected from the group consisting of halo, cyano, hydroxy,        —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl-O—, C₁₋₆alkyl-S—, aryl,        heterocyclyl, and C₃₋₁₀cycloalkyl, or from the formula:

-   -   even more in particular R²¹ is selected from the group        consisting of C₁₋₂₀alkyl; C₃₋₁₀cycloalkyl; and optionally        substituted aryl; wherein said C₁₋₂₀alkyl is substituted with a        substituent selected from the group consisting of halo,        —O—C(═O)—C₁₋₆alkyl, or from the formula:

heterocyclyl as used herein is selected from the group consisting ofpiperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl,1,3-dioxanyl, 3-dioxolanyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyland hexahydrofuro[3,2-b]furanyl; in particular piperidinyl,1,3-dioxanyl, indolinyl, tetrahydropyranyl and tetrahydrofuranyl;

optionally substituted C₃₋₁₀cycloalkyl as used herein is selected fromthe group consisting of cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, adamantanyl,bicyclo(2.2.1)heptanyl and cyclodecyl with cyclopropyl, cyclopentyl,cyclohexyl, adamantanyl, and bicyclo(2.2.1)heptanyl being particularlypreferred; wherein said C₃₋₁₀cycloalkyl is optionally substituted with1, 2, 3, or more in particular 1, 2 or 3; more in particular 1 or 2;even more in particular 1 substituent selected from halogen, hydroxyl,oxo, nitro, amino, cyano, C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy, or—SO₂—NH₂,

optionally substituted heterocyclyl as used herein is selected from thegroup consisting of piperidinyl, pyrrolidinyl, morpholinyl,thiomorpholinyl, piperazinyl, 1,3-dioxanyl, 3-dioxolanyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolinyl,tetrahydropyranyl, tetrahydrofuranyl and hexahydrofuro[3,2-b]furanyl; inparticular piperidinyl, 1,3-dioxanyl, indolinyl, tetrahydropyranyl andtetrahydrofuranyl; wherein said heterocyclyl is optionally substitutedwith 1, 2, 3 or more; in particular 1 substituent selected from thegroup consisting of halogen, hydroxyl, oxo, nitro, amino, hydrazine,aminocarbonyl, azido, cyano, alkyl, cycloalkyl, alkenyl, alkynyl,cycloalkylalkyl, alkylamino, alkoxy, —SO₂—NH₂, aryl, heteroaryl,aralkyl, haloalkyl, haloalkoxy, alkoxycarbonyl, alkylaminocarbonyl,heteroarylalkyl, alkylsulfonamide, heterocyclyl,alkylcarbonylaminoalkyl, aryloxy, alkylcarbonyl, acyl, arylcarbonyl,aminocarbonyl, alkylsulfoxide, —SO₂R^(a), alkylthio, carboxyl, and thelike, wherein R^(a) is alkyl or cycloalkyl; preferably selected fromhalogen, hydroxyl, oxo, nitro, amino, cyano, C₁₋₄alkyl, C₃₋₆cycloalkyl,C₁₋₄alkoxy, or —SO₂—NH₂,

aryl as used herein is selected from the group consisting of phenyl,naphtyl, 1,4-dihydro naphtyl, or 1,2,3,4-tetrahydronaphtyl wherein saidaryl is optionally substituted with 1, 2, 3, 4 or 5 substituentsselected from halogen, nitro, C₁₋₄alkyl, C₁₋₄alkyloxy, or C₁₋₄alkylthio;in particular phenyl or 1,2,3,4-tetrahydronaphtyl wherein said aryl isoptionally substituted with 1, 2, 3, 4 or 5 substituents selected fromhalogen, oxo, nitro, C₁₋₄alkyl, C₁₋₄alkyloxy, or C₁₋₄alkylthio; more inparticular phenyl optionally substituted with 1, 2, 3, 4 or 5substituents selected from halogen, nitro, C₁₋₄alkyl, C₁₋₄alkyloxy, orC₁₋₄alkylthio;

heteroaryl as used herein is selected from the group consisting offuranyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, benzopyranyl,1(4H)-benzopyranyl, 1(2H)-benzopyranyl, 3,4-dihydro-1(2H)-benzopyranyl,and 2,3-dihydro-1(4H)-benzopyranyl wherein said heteroaryl is optionallysubstituted with 1, 2, 3, 4 or 5 substituents selected from halogen,oxo, nitro, C₁₋₄alkyl, C₁₋₄alkyloxy, or C₁₋₄alkylthio; in particularfuranyl, thiohenyl, pyridinyl, benzopyranyl, 1(2H)-benzopyranyl,3,4-dihydro-1(2H)-benzopyranyl, and 2,3-dihydro-1(4H)-benzopyranylwherein said heteroaryl is optionally substituted with 1, 2, 3, 4 or 5substituents selected from halogen, oxo, or C₁₋₄alkyl;

L is at the meta or para position of the phenyl ring vis-à-vis thebinding of said phenyl ring to the remainder of the molecule in analogywith the —COOR²¹ group shown in formulae IIa and IIb;

the proviso that when L is a direct bond and T is —O—R²¹, and whereinR²¹ is an unsubstituted C₁₋₂₀alkyl, said L-(C═O)-T is bond at the metaor para position of the phenyl ring vis-à-vis the binding of said phenylring to the remainder of the molecule in analogy with the —COOR²¹ groupshown in formulae IIa and IIb.

An interesting group of compounds, are those compounds of the presentinvention presented by formula Ib

wherein;R¹ is selected form the group comprising hydrogen, C₁₋₄alkyl orC₃₋₆cycloalkyl;Ar is selected from the group comprising:

Wherein X is selected from the group comprising hydrogen or halo;

Z is a bivalent radical selected from the group consisting of —O—;—NR⁵—; and —NR⁵—C(═O)—;W represents C₁₋₆alkyl substituted with a substituent selected from—O-Het²; —S-Het³; or C(═O)—NR³R⁴; andwherein R³, R⁴, R⁵, Het² and Het³ are defined as for any one of theaforementioned embodiments of the compounds of formula I or Iahereinbefore.

In one embodiment of the present invention the compounds of formula Ibare further characterized in that

R³ is selected from the group consisting of hydrogen; C₁₋₂₀alkyloptionally substituted with 1, 2 or 3 substituents each independentlyselected from the group consisting of —C(═O)—OR²¹; —C(═O)—SR²²;—C(═O)—NR⁷R⁸; Het¹; —O-Het²; —S-Het³; C₁₋₆alkyl-S— and C₁₋₆alkyl-O—; inparticular R³ is hydrogen;

R⁴ is selected from the group consisting of C₁₋₂₀alkyl substituted with1, 2 or 3 substituents each independently selected from the groupconsisting of —C(═O)—OR²¹; —C(═O)—SR²²; —C(═O)—NR⁷R⁸; Het¹; —O-Het²;—S-Het³; C₁₋₆alkyl-S— and C₁₋₆alkyl-O—; more in particular R⁴ isselected from the group consisting of C₁₋₂₀alkyl substituted with 1, 2or 3 substituents each independently selected from the group consistingof —C(═O)—OR²¹; —C(═O)—SR²²; —C(═O)—NR⁷R⁸; Het¹; —O-Het²; and —S-Het³;or;

R³ and R⁴ together with the nitrogen atom to which they are attachedform a heterocycle substituted with one substituent selected from thegroup consisting of —C(═O)—OR²¹; —C(═O)—SR²²; —C(═O)—NR⁹R¹⁰; Het¹;—O-Het²; —S-Het³; or C₁₋₆alkyl wherein said C₁₋₆alkyl is substitutedwith 1, 2, or 3 substituents each independently selected from the groupconsisting of —C(═O)—OR²¹; —C(═O)—SR²²; —C(═O)—NR⁹R¹⁰; Het¹; —O-Het²;and —S-Het³; in particular R³ and R⁴ together with the nitrogen atom towhich they are attached form a heterocycle substituted with onesubstituent selected from the group consisting of —C(═O)—OR²¹;—C(═O)—SR²²; —C(═O)—NR⁹R¹⁰; Het¹; or C₁₋₆alkyl wherein said C₁₋₆alkyl issubstituted with 1, 2, or 3 substituents each independently selectedfrom the group consisting of Het¹; —O-Het²; and —S-Het³;

R⁵ is hydrogen;

R⁷ or R⁸ are independently selected from the group consisting ofhydrogen; or C₁₋₆alkyl substituted with 1, 2, or 3 substituents eachindependently selected from the group consisting of aryl, heteroaryl,C₃₋₆cycloalkenyl, —C(═O)—OR²¹; and —C(═O)—NH₂; in particular R⁷ or R⁸are independently selected from the group consisting of hydrogen; orC₁₋₆alkyl substituted with 1, 2, or 3 substituents each independentlyselected from the group consisting of —C(═O)—OR²¹; and —C(═O)—NH₂;

R⁹ or R¹⁰ are independently selected from the group consisting ofhydrogen; or C₁₋₆alkyl substituted with 1, 2, or 3, —C(═O)—OR²¹substituents;

R¹³ or R¹⁴ are independently selected from the group consisting ofhydrogen; C₁₋₆alkyl; C₁₋₆alkyl; C₁₋₆alkyl-O—C₁₋₆alkyl-;C₁₋₆alkyl-S—C₁₋₆alkyl-; or C₁₋₆alkyl-C(═O)— and wherein each of saidC₁₋₆alkyl; C₁₋₆alkyl-O—C₁₋₆alkyl-; C₁₋₆alkyl-S—C₁₋₆alkyl-; orC₁₋₆alkyl-C(═O)— is substituted with 1, 2, or 3 substituents eachindependently selected from the group consisting of —C(═O)—OR²¹;—C(═O)—SR²²; Het¹; —O-Het²; and —S-Het³;

R²¹ is selected from the group consisting of C₁₋₂₀alkyl; C₁₋₂₀alkenyl;C₁₋₂₀alkynyl; optionally substituted C₃₋₁₅cycloalkyl; optionallysubstituted heterocyclyl; and optionally substituted aryl;

-   -   wherein said C₁₋₂₀alkyl is optionally substituted with 1, 2, 3        or more substituents selected from the group consisting of halo,        cyano, hydroxy, aryl-O—, aryl-S—, aryl-S(═O)₂—, aryl-C(═O),        —C(═O)—NR¹³R¹⁴, —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl-O—, C₁₋₆alkyl-S—,        aryl, heteroaryl, heterocyclyl and C₃₋₁₅cycloalkyl or from the        formula:

or

R²¹ taken together with the oxycarbonyl and phenyl to which it isattached forms a cyclic ester consisting of

wherein q is an integer from 1 to 6;

R²² is C₁₋₂₀alkyl optionally substituted with 1, 2, 3 or more halosubstituents;

Het¹, Het² or Het³ are independently selected from the group comprising;

In a further embodiment the present invention provides those compoundsof formula (Ib) wherein one or more of the following restrictions apply;

R³ is hydrogen;

R⁴ is —C₁₋₆alkyl substituted with a substituent selected from —O-Het²,or —S-Het³; with in a particular embodiment said Het² or Het³ beingselected from the group consisting of

In a preferred embodiment the present invention provides compounds offormula IIa, IIIa, IVa, Va, VIa, VIIa, VIIIa, IXa, Xa, IIb, IIIb, IVb,Vb, VIb, VIIb, VIIIb, IXb, Xb, XI, XII, XIII, XIV, XV, XVI, XVII,XVIIIa, XIXa, XXa, XXIa, XXIb, XXIIa, XXIIIa or XXIVa.

wherein;q is an integer from 2 to 6;

R¹¹ is a substituted C₁₋₆alkyl, or a substituted —C₂₋₈alkenyl; said—C₁₋₆alkyl and —C₂₋₈alkenyl each independently substituted with asubstituent selected from the group consisting of C(═O)—OR²¹;—C(═O)—SR²²; —C(═O)—NR³R⁴; Het¹; —O-Het²; and —S-Het³;

R¹² is a substituted C₁₋₆alkyl, a substituted C₁₋₆alkyl-S—C₁₋₆alkyl or asubstituted —C₂₋₈alkenyl; said —C₁₋₆alkyl, C₁₋₆alkyl-S—C₁₋₆alkyl and—C₂₋₈alkenyl each independently substituted with 1, 2, or 3 substituentseach independently selected from the group consisting of aryl,heteroaryl, C₃₋₆cycloalkenyl, —C(═O)—OR²¹; —C(═O)—SR²²; Het¹; —O-Het²;and —S-Het³; and

wherein Ar, R¹, R²¹, R²², R³, R⁴, R⁵, R⁶, Het¹, Het² and Het³ have thesame meanings than those defined herein before.

The compounds of the present invention can be prepared according to thereaction schemes provided in the examples hereinafter, but those skilledin the art will appreciate that these are only illustrative for theinvention and that the compounds of this invention can be prepared byany of several standard synthetic processes commonly used by thoseskilled in the art of organic chemistry.

In a preferred embodiment, the compounds of the present invention areuseful as kinase inhibitors, more in particular for the inhibition of atleast one ROCK kinase, selected from ROCKI and ROCKII, in particularsoft ROCK inhibitors.

The present invention further provides the use of a compound as definedhereinbefore or the use of a composition comprising said compound, as ahuman or veterinary medicine, in particular for prevention and/ortreatment of at least one disease or disorder, in which ROCK isinvolved, such as diseases linked to smooth muscle cell function,inflammation, fibrosis, excessive cell proliferation, excessiveangiogenesis, hyperreactivity, barrier dysfunction, neurodegeration,function, inflammation, fibrosis, excessive cell proliferation,excessive angiogenesis, hyperreactivity, barrier dysfunction,neurodegeration and remodeling.

In a further embodiment, the invention provides the use of a compound asdefined hereinbefore, or the use of a composition comprising saidcompound in the prevention and/or treatment of at least one disease ordisorder selected from the group comprising eye diseases; airwaydiseases; throat, nose and ear diseases; intestinal diseases;cardiovascular and vascular diseases; inflammatory diseases;neurological and CNS disorders: proliferative diseases; kidney diseases;sexual dysfunction; blood diseases; bone diseases; diabetes; benignprostatic hyperplasia, transplant rejection, liver disease, systemiclupus erythematosus, spasm, hypertension, chronic obstructive bladderdisease, premature birth, infection, allergy, obesity, pancreaticdisease and AIDS.

In a preferred embodiment, the invention provides the use of a compoundas defined hereinbefore or the use of a composition comprising saidcompound in the prevention and/or treatment of eyes diseases includingbut not limited to retinopathy, optic neuropathy, glaucoma anddegenerative retinal diseases such as macular degeneration, retinitispigmentosa and inflammatory eye diseases, and/or for preventing,treating and/or alleviating complications and/or symptoms associatedtherewith.

In particular those compounds selected from the group consisting of;

Those compounds of formula I wherein; Y is an aryl or heteroarylsubstituted with a substituent selected from the group consisting of—C(═O)—OR²¹; —C(═O)—SR²²; —C(═O)—NR³R⁴; —O—C₁₋₆alkyl; or —C₁₋₆alkyl;wherein said —O—C₁₋₆alkyl or —C₁₋₆alkyl are each independentlysubstituted with a substituent selected from the group consisting of—C(═O)—OR²¹, and Het¹; and R⁴ is —C₁₋₆alkyl substituted with asubstituent selected from —C(═O)—OR²¹, —C(═O)—SR²², or Het¹; and

Those compounds of formula Ia wherein Ar represents

wherein X is hydrogen or halo;

L is a direct bond, C₁₋₄alkyl, or —O—C₁₋₄alkyl;

T is —O—R²¹ or —NR³R⁴;

R¹ represents hydrogen or C₁₋₄alkyl;

R³ is hydrogen;

R⁴ is —C₁₋₆alkyl substituted with a substituent selected from—C(═O)—OR²¹, —C(═O)—SR²², —C(═O)—NR⁷R⁸, or Het¹; in particular—C₁₋₆alkyl substituted with a substituent selected from —C(═O)—OR²¹, orHet¹; with in a particular embodiment said R²¹ being a —C₁₋₆alkyl ; or

R³ and R⁴ together with the nitrogen atom to which they are attachedform a heterocycle substituted with C₁₋₆alkyl wherein said C₁₋₆alkyl issubstituted with 1, 2, or 3 substituents each independently selectedfrom the group consisting of —C(═O)—OR²¹; and —C(═O)—NR⁹R¹⁰;

R⁹ or R¹⁰ are independently selected from the group consisting ofhydrogen; or C₁₋₆alkyl substituted with 1, 2, or 3, —C(═O)—OR²¹substituents;

R²¹ is selected from the group consisting of C₁₋₂₀alkyl; optionallysubstituted C₃₋₁₀cycloalkyl; optionally substituted aryl; and optionallysubstituted heterocyclyl; wherein said C₁₋₂₀alkyl is optionallysubstituted with a substituent selected from the group consisting ofhalo, cyano, hydroxy, —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl-O—, C₁₋₆alkyl-S—,aryl, heterocyclyl, and C₃₋₁₀cycloalkyl, or from the formula:

heterocyclyl as used herein is selected from the group consisting ofpiperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl,1,3-dioxanyl, 3-dioxolanyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyland hexahydrofuro[3,2-b]furanyl; in particular piperidinyl,1,3-dioxanyl, indolinyl, tetrahydropyranyl and tetrahydrofuranyl;

optionally substituted C₃₋₁₀cycloalkyl as used herein is selected fromthe group consisting of cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, adamantanyl,bicyclo(2.2.1)heptanyl and cyclodecyl with cyclopropyl, cyclopentyl,cyclohexyl, adamantanyl, and bicyclo(2.2.1)heptanyl being particularlypreferred; wherein said C₃₋₁₀cycloalkyl is optionally substituted with1, 2, 3, or more in particular 1, 2 or 3; more in particular 1 or 2;even more in particular 1 substituent selected from halogen, hydroxyl,oxo, nitro, amino, cyano, C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy, or—SO₂—NH₂,

optionally substituted heterocyclyl as used herein is selected from thegroup consisting of piperidinyl, pyrrolidinyl, morpholinyl,thiomorpholinyl, piperazinyl, 1,3-dioxanyl, 3-dioxolanyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolinyl,tetrahydropyranyl, tetrahydrofuranyl and hexahydrofuro[3,2-b]furanyl; inparticular piperidinyl, 1,3-dioxanyl, indolinyl, tetrahydropyranyl andtetrahydrofuranyl; wherein said heterocyclyl is optionally substitutedwith 1, 2, 3 or more; in particular 1 substituent selected from thegroup consisting of halogen, hydroxyl, oxo, nitro, amino, hydrazine,aminocarbonyl, azido, cyano, alkyl, cycloalkyl, alkenyl, alkynyl,cycloalkylalkyl, alkylamino, alkoxy, —SO₂—NH₂, aryl, heteroaryl,aralkyl, haloalkyl, haloalkoxy, alkoxycarbonyl, alkylaminocarbonyl,heteroarylalkyl, alkylsulfonamide, heterocyclyl,alkylcarbonylaminoalkyl, aryloxy, alkylcarbonyl, acyl, arylcarbonyl,aminocarbonyl, alkylsulfoxide, —SO₂Ra, alkylthio, carboxyl, and thelike, wherein R^(a) is alkyl or cycloalkyl; preferably selected fromhalogen, hydroxyl, oxo, nitro, amino, cyano, C₁₋₄alkyl, C₃₋₆cycloalkyl,C₁₋₄alkoxy, or —SO₂—NH₂,

aryl as used herein is selected from the group consisting of phenyl,naphtyl, 1,4-dihydro naphtyl, or 1,2,3,4-tetrahydronaphtyl wherein saidaryl is optionally substituted with 1, 2, 3, 4 or 5 substituentsselected from halogen, nitro, C₁₋₄alkyl, C₁₋₄alkyloxy, or C₁₋₄alkylthio;in particular phenyl or 1,2,3,4-tetrahydronaphtyl wherein said aryl isoptionally substituted with 1, 2, 3, 4 or 5 substituents selected fromhalogen, oxo, nitro, C₁₋₄alkyl, C₁₋₄alkyloxy, or C₁₋₄alkylthio; more inparticular phenyl optionally substituted with 1, 2, 3, 4 or 5substituents selected from halogen, nitro, C₁₋₄alkyl, C₁₋₄alkyloxy, orC₁₋₄alkylthio;

heteroaryl as used herein is selected from the group consisting offuranyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, benzopyranyl,1(4H)-benzopyranyl, 1(2H)-benzopyranyl, 3,4-dihydro-1(2H)-benzopyranyl,and 2,3-dihydro-1(4H)-benzopyranyl wherein said heteroaryl is optionallysubstituted with 1, 2, 3, 4 or 5 substituents selected from halogen,oxo, nitro, C₁₋₄alkyl, C₁₋₄alkyloxy, or C₁₋₄alkylthio; in particularfuranyl, thiohenyl, pyridinyl, benzopyranyl, 1(2H)-benzopyranyl,3,4-dihydro-1(2H)-benzopyranyl, and 2,3-dihydro-1(4H)-benzopyranylwherein said heteroaryl is optionally substituted with 1, 2, 3, 4 or 5substituents selected from halogen, oxo, or C₁₋₄alkyl;

are particularly useful in the prevention and/or treatment of eyesdiseases including but not limited to retinopathy, optic neuropathy,glaucoma and degenerative retinal diseases such as macular degeneration,retinitis pigmentosa and inflammatory eye diseases, and/or forpreventing, treating and/or alleviating complications and/or symptomsassociated therewith. It is accordingly an object of the presentinvention to provide said compounds for use in the treatment of eyesdiseases including but not limited to retinopathy, optic neuropathy,glaucoma and degenerative retinal diseases such as macular degeneration,retinitis pigmentosa and inflammatory eye diseases, and/or forpreventing, treating and/or alleviating complications and/or symptomsassociated therewith; more in particular in the treatment of glaucoma.Alternatively, to provide a method for prevention and/or treatment ofeye diseases selected from the group consisting of retinopathy, opticneuropathy, glaucoma, inflammatory eye diseases and degenerative retinaldiseases such as macular degeneration and retinitis pigmentosa;preferably glaucoma; said method comprising administering to a subjectin need thereof a therapeutic effective amount of a compound accordingto formula I; in particular a compound as defined hereinbefore.

In another preferred embodiment, the invention provides the use of acompound as defined hereinbefore or the use of a composition comprisingsaid compound in the prevention and/or treatment of airway diseases;including but not limited to pulmonary fibrosis, emphysema, chronicbronchitis, asthma, fibrosis, pneumonia, cystic fibrosis, chronicobstructive pulmonary disease (COPD); bronchitis and rhinitis andrespiratory distress syndrome, and/or for preventing, treating and/oralleviating complications and/or symptoms associated therewith.

In particular those compounds selected from the group consisting of;

Those compounds of formula I wherein; Y is an aryl or heteroarylsubstituted with a substituent selected from the group consisting of—C(═O)—NR³R⁴; —NR⁵R⁶; —O—C₁₋₆alkyl; or —C₁₋₆alkyl; wherein said—O—C₁₋₆alkyl or —C₁₋₆alkyl are each independently substituted with asubstituent selected from the group consisting of —C(═O)—NR³R⁴, —O-Het²and S-Het³; with in a particular embodiment said Het² or Het³independently being selected from the group comprising

and

Those compounds of formula Ia wherein; Ar represents

wherein X is hydrogen or halo;

L is a direct bond, C₁₋₄alkyl, or —O—C₁₋₄alkyl;

T is —O—R²¹ or —NR³R⁴;

R¹ represents hydrogen or C₁₋₄alkyl;

R³ is hydrogen;

R⁴ is —C₁₋₆alkyl substituted with a substituent selected from —O-Het²,or —S-Het³; with in a particular embodiment said Het² or Het³ beingselected from the group consisting of

Het² or Het³ are independently selected from the group comprising;

and

Those compounds of formula Ib;

are particularly useful in the prevention and/or treatment of airwaydiseases; including but not limited to pulmonary fibrosis, emphysema,chronic bronchitis, asthma, fibrosis, pneumonia, cystic fibrosis,chronic obstructive pulmonary disease (COPD); bronchitis and rhinitisand respiratory distress syndrome, and/or for preventing, treatingand/or alleviating complications and/or symptoms associated therewith.It is accordingly an object of the present invention to provide saidcompounds for use in the treatment of airway diseases; including but notlimited to pulmonary fibrosis, emphysema, chronic bronchitis, asthma,fibrosis, pneumonia, cystic fibrosis, chronic obstructive pulmonarydisease (COPD); bronchitis and rhinitis and respiratory distresssyndrome, and/or for preventing, treating and/or alleviatingcomplications and/or symptoms associated therewith. Alternatively, toprovide a method for prevention and/or treatment of airway diseases;including but not limited to pulmonary fibrosis, emphysema, chronicbronchitis, asthma, fibrosis, pneumonia, cystic fibrosis, chronicobstructive pulmonary disease (COPD); bronchitis and rhinitis andrespiratory distress syndrome, said said method comprising administeringto a subject in need thereof a therapeutic effective amount of acompound according to formula I; in particular a compound as definedhereinbefore.

In a further embodiment, the invention provides the use of a compound asdefined hereinbefore or the use of a composition comprising saidcompound in the prevention and/or treatment of cardiovascular andvascular diseases: including but not limited to cerebrovascularcontraction, reperfusion, hypoxia peripheral circulation disorder,myocardial hypertrophy, acute stroke, congestive heart failure,cardiovascular ischemia, heart disease, cardiac remodeling, angina,coronary vasospasm, cerebral vasospasm, restenosis, hypertension,pulmonary hypertension, pulmonary vasoconstriction, arteriosclerosis,atherosclerosis, aneurism, hemorrhage, Raynaud's disorder, thrombosis(including deep thrombosis) and platelet related diseases, and/or forpreventing, treating and/or alleviating complications and/or symptomsassociated therewith and/or alleviating complications and/or symptomsassociated therewith.

In a further embodiment, the invention provides the use of a compound asdefined hereinbefore or the use of a composition comprising saidcompound in the prevention and/or treatment of Throat, Nose and Eardiseases: including but not limited to sinus problems, hearing problems,toothache, tonsillitis, ulcer and rhinitis.

In a further embodiment, the invention provides the use of a compound asdefined hereinbefore or the use of a composition comprising saidcompound in the prevention and/or treatment of skin diseases: includingbut not limited to hyperkeratosis, parakeratosis, hypergranulosis,acanthosis, dyskeratosis, spongiosis and ulceration.

In a further embodiment, the invention provides the use of a compound asdefined hereinbefore or the use of a composition comprising saidcompound in the prevention and/or treatment of Intestinal diseases;including but not limited to inflammatory bowel disease (IBD), colitis,gastroenteritis, ileus, ileitis, appendicitis and Crohn's disease.

In yet another embodiment, the invention provides the use of a compoundas defined hereinbefore or the use of a composition comprising saidcompound in the prevention and/or treatment of inflammatory diseases:including but not limited to contact dermatitis, atopic dermatitis,psoriasis, rheumatoid arthritis, juvenile rheumatoid arthritis,ankylosing spondylitis, psoriatic arthritis, inflammatory bowel disease,Crohn's disease and ulcerative colitis, and/or for preventing, treatingand/or alleviating complications and/or symptoms and/or inflammatoryresponses associated therewith.

In another embodiment, the invention provides the use of a compound asdefined hereinbefore or the use of a composition comprising saidcompound in the prevention, treatment and/or management of neurologicaland CNS disorders: including but not limited to stroke, meningitis,convulsions, brain or spinal cord injury and inflammatory anddemyelinating diseases such as Alzheimer's disease, multiple sclerosisand neuropathic pain. The present compounds are therefore suitable forpreventing neurodegeneration and stimulating neurogeneration in variousneurological disorders, and/or for preventing, treating and/oralleviating complications and/or symptoms associated therewith.

In another embodiment, the invention provides the use of a compound asdefined hereinbefore or the use of a composition comprising saidcompound in the prevention and/or treatment of proliferative diseases:such as but not limited to cancer of the brain (gliomas), breast, colon,intestine, skin, head and neck, nerve, uterus, kidney, lung, liver,ovary, pancreas, prostate, or thyroid gland; Castleman disease;leukemia; sarcoma; lymphoma; malignoma; and melanoma; and/or forpreventing, treating and/or alleviating complications and/or symptomsand/or inflammatory responses associated therewith.

In another embodiment, the invention provides the use of a compound asdefined hereinbefore or the use of a composition comprising saidcompound in the prevention and/or treatment of kidney diseases:including but not limited to renal fibrosis or renal dysfunction; and/orfor preventing, treating and/or alleviating complications and/orsymptoms and/or inflammatory responses associated therewith.

In another embodiment, the invention provides the use of a compound asdefined hereinbefore or the use of a composition comprising saidcompound in the prevention and/or treatment of sexual dysfunction:including but not limited to hypogonadism, bladder disease,hypertension, diabetes, or pelvic surgery; and/or to treat sexualdysfunction associated with treatment using certain drugs, such as drugsused to treat hypertension, depression or anxiety.

In another embodiment, the invention provides the use of a compound asdefined hereinbefore or the use of a composition comprising saidcompound in the prevention and/or treatment of blood diseases: includingbut not limited to sepsis, eosinophilia, endotoxemia; and/or forpreventing, treating and/or alleviating complications and/or symptomsand/or inflammatory responses associated therewith.

In another embodiment, the invention provides the use of a compound asdefined hereinbefore or the use of a composition comprising saidcompound in the prevention and/or treatment of bone diseases: includingbut not limited to osteoporosis and osteoarthritis; and/or forpreventing, treating and/or alleviating complications and/or symptomsand/or inflammatory responses associated therewith.

In another embodiment, the invention provides the use of a compound asdefined hereinbefore or the use of a composition comprising saidcompound in the prevention and/or treatment of diabetes: including butnot limited to hyperglycemia and type 1 diabetes; and/or for preventing,treating and/or alleviating complications and/or symptoms and/orinflammatory responses associated therewith.

In another embodiment, the invention provides the use of a compound asdefined hereinbefore or the use of a composition comprising saidcompound in the prevention and/or treatment of diseases and disorderssuch as benign prostatic hyperplasia, transplant rejection, liverdisease, systemic lupus erythmatosis, spasm, hypertension, chronicobstructive bladder disease, premature birth, infection, allergy,obesity, pancreatic disease and AIDS, and/or for preventing, treatingand/or alleviating complications and/or symptoms associated therewith.

In a preferred embodiment the present invention provides the use of acompound as defined hereinbefore or the use of a composition comprisingsaid compound in the prevention and/or treatment of glaucoma, asthma,sexual dysfunction or COPD.

The present invention further provides a compound as definedhereinbefore or a composition comprising said compound for use in theprevention and/or treatment of at least one disease or disorder selectedfrom the group comprising eye diseases; airway diseases; cardiovascularand vascular diseases; inflammatory diseases; neurological and CNSdisorders: proliferative diseases; kidney diseases; sexual dysfunction;blood diseases; bone diseases; diabetes; benign prostatic hyperplasia,transplant rejection, liver disease, systemic lupus erythematosus,spasm, hypertension, chronic obstructive bladder disease, prematurebirth, infection, allergy, obesity, pancreatic disease and AIDS.

In a preferred embodiment, the invention provides a compound as definedhereinbefore or a composition comprising said compound for use in theprevention and/or treatment of eyes diseases including but not limitedto retinopathy, optic neuropathy, glaucoma and degenerative retinaldiseases such as macular degeneration, retinitis pigmentosa andinflammatory eye diseases, and/or for preventing, treating and/oralleviating complications and/or symptoms associated therewith.

In another preferred embodiment, the invention provides a compound asdefined hereinbefore or a composition comprising said compound for usein the prevention and/or treatment of airway diseases; including but notlimited to pulmonary fibrosis, emphysema, chronic bronchitis, asthma,fibrosis, pneumonia, cystic fibrosis, chronic obstructive pulmonarydisease (COPD); bronchitis and rhinitis and respiratory distresssyndrome, and/or for preventing, treating and/or alleviatingcomplications and/or symptoms associated therewith.

In a further embodiment, the invention provides a compound as definedhereinbefore or a composition comprising said compound for use in theprevention and/or treatment of cardiovascular and vascular diseases:including but not limited to cerebrovascular contraction, reperfusion,hypoxia peripheral circulation disorder, myocardial hypertrophyacutestroke, congestive heart failure, cardiovascular ischemia, heartdisease, cardiac remodeling, angina, coronary vasospasm, cerebralvasospasm, restenosis, hypertension, pulmonary hypertension, pulmonaryvasoconstriction, arteriosclerosis, atherosclerosis, aneurism,hemorrhage, Raynaud's disorder, thrombosis (including deep thrombosis)and platelet related diseases, and/or for preventing, treating and/oralleviating complications and/or symptoms associated therewith and/oralleviating complications and/or symptoms associated therewith.

In yet another embodiment, the invention provides a compound as definedhereinbefore or a composition comprising said compound for use in theprevention and/or treatment of inflammatory diseases: including but notlimited to contact dermatitis, atopic dermatitis, psoriasis, rheumatoidarthritis, juvenile rheumatoid arthritis, ankylosing spondylitis,psoriatic arthritis, inflammatory bowel disease, Crohn's disease andulcerative colitis, and/or for preventing, treating and/or alleviatingcomplications and/or symptoms and/or inflammatory responses associatedtherewith.

In another embodiment, the invention provides a compound as definedhereinbefore or a composition comprising said compound for use in theprevention and/or treatment of neurological and CNS disorders: includingbut not limited to stroke, meningitis, convulsions, brain or spinal cordinjury and inflammatory and demyelinating diseases such as Alzheimer'sdisease, multiple sclerosis and neuropathic pain. The present compoundsare therefore suitable for preventing neurodegeneration and stimulatingneurogeneration in various neurological disorders, and/or forpreventing, treating and/or alleviating complications and/or symptomsassociated therewith.

In another embodiment, the invention provides a compound as definedhereinbefore or a composition comprising said compound for use in theprevention and/or treatment of proliferative diseases: such as but notlimited to cancer of the brain (gliomas), breast, colon, intestine,skin, head and neck, nerve, uterus, kidney, lung, liver, ovary,pancreas, prostate, or thyroid gland; Castleman disease; leukemia;sarcoma; lymphoma; malignoma; and melanoma; and/or for preventing,treating and/or alleviating complications and/or symptoms and/orinflammatory responses associated therewith.

In another embodiment, the invention provides a compound as definedhereinbefore or a composition comprising said compound for use in theprevention and/or treatment of kidney diseases: including but notlimited to renal fibrosis or renal dysfunction; and/or for preventing,treating and/or alleviating complications and/or symptoms and/orinflammatory responses associated therewith.

In another embodiment, the invention provides the use of a compound asdefined hereinbefore or the use of a composition comprising saidcompound in the preparation of a medicament for the prevention and/ortreatment of sexual dysfunction: including but not limited tohypogonadism, bladder disease, hypertension, diabetes, or pelvicsurgery; and/or to treat sexual dysfunction associated with treatmentusing certain drugs, such as drugs used to treat hypertension,depression or anxiety.

In another embodiment, the invention provides a compound as definedhereinbefore or a composition comprising said compound for use in theprevention and/or treatment of blood diseases: including but not limitedto sepsis, eosinophilia, endotoxemia; and/or for preventing, treatingand/or alleviating complications and/or symptoms and/or inflammatoryresponses associated therewith.

In another embodiment, the invention provides a compound as definedhereinbefore or a composition comprising said compound for use in theprevention and/or treatment of bone diseases: including but not limitedto osteoporosis and osteoarthritis; and/or for preventing, treatingand/or alleviating complications and/or symptoms and/or inflammatoryresponses associated therewith.

In another embodiment, the invention provides a compound as definedhereinbefore or a composition comprising said compound for use in theprevention and/or treatment of diabetes: including but not limited tohyperglycemia and type 1 diabetes; and/or for preventing, treatingand/or alleviating complications and/or symptoms and/or inflammatoryresponses associated therewith.

In another embodiment, the invention provides a compound as definedhereinbefore or a composition comprising said compound for use in theprevention and/or treatment of diseases and disorders such as benignprostatic hyperplasia, transplant rejection, liver disease, systemiclupus erythematosus, spasm, hypertension, chronic obstructive bladderdisease, premature birth, infection, allergy, obesity, pancreaticdisease and AIDS, and/or for preventing, treating and/or alleviatingcomplications and/or symptoms associated therewith.

In a preferred embodiment the present invention provides a compound asdefined hereinbefore or a composition comprising said compound for usein the prevention and/or treatment of glaucoma, asthma, sexualdysfunction or COPD.

Method of Treatment

The present invention further provides a method for the preventionand/or treatment of at least one disease or disorder selected from thegroup comprising eye diseases; airway diseases; cardiovascular andvascular diseases; inflammatory diseases; neurological and CNSdisorders: proliferative diseases; kidney diseases; sexual dysfunction;blood diseases; bone diseases; diabetes; benign prostatic hyperplasia;transplant rejection; liver disease; systemic lupus erythematosus;spasm; hypertension; chronic obstructive bladder disease; prematurebirth; infection; allergy; obesity; pancreatic disease; and AIDS; saidmethod comprising administering to a subject in need thereof atherapeutic effective amount of a compound or a composition as definedherein.

In a preferred embodiment, the invention provides a method for theprevention and/or treatment of eye diseases including but not limited toretinopathy, optic neuropathy, glaucoma and degenerative retinaldiseases such as macular degeneration, retinitis pigmentosa andinflammatory eye diseases; said method comprising administering to asubject in need thereof a therapeutic effective amount of a compound ora composition as defined herein.

In another preferred embodiment, the invention provides a method for theprevention and/or treatment of airway diseases including but not limitedto pulmonary fibrosis, emphysema, chronic bronchitis, asthma, fibrosis,pneumonia, cystic fibrosis, chronic obstructive pulmonary disease (COPD)bronchitis, rhinitis, and respiratory distress syndrome; said methodcomprising administering to a subject in need thereof a therapeuticeffective amount of a compound or a composition as defined herein.

In another embodiment, the invention provides a method for theprevention and/or treatment of cardiovascular and vascular diseases:including but not limited to cerebrovascular contraction, reperfusion,hypoxia peripheral circulation disorder, myocardial hypertrophyacutestroke, congestive heart failure, cardiovascular ischemia, heartdisease, cardiac remodeling, angina, coronary vasospasm, cerebralvasospasm, restenosis, hypertension, pulmonary hypertension, pulmonaryvasoconstriction, arteriosclerosis, atherosclerosis, aneurism,hemorrhage, Raynaud's disorder, thrombosis (including deep thrombosis)and platelet related diseases; said method comprising administering to asubject in need thereof a therapeutic effective amount of a compound ora composition as defined herein.

In another embodiment, the invention provides a method for theprevention and/or treatment of inflammatory diseases: including but notlimited to contact dermatitis, atopic dermatitis, psoriasis, rheumatoidarthritis, juvenile rheumatoid arthritis, ankylosing spondylitis,psoriatic arthritis, inflammatory bowel disease, Crohn's disease andulcerative colitis; said method comprising administering to a subject inneed thereof a therapeutic effective amount of a compound or acomposition as defined herein.

In another embodiment, the invention provides a method for theprevention and/or treatment of neurological and CNS disorders: includingbut not limited to stroke, meningitis, convulsions, brain or spinal cordinjury and inflammatory and demyelinating diseases such as Alzheimer'sdisease, multiple sclerosis and neuropathic pain. The present compoundsare therefore suitable for preventing neurodegeneration and stimulatingneurogeneration in various neurological disorders; said methodcomprising administering to a subject in need thereof a therapeuticeffective amount of a compound or a composition as defined herein.

In another embodiment, the invention provides a method for theprevention and/or treatment of proliferative diseases: such as but notlimited to cancer of the brain (gliomas), breast, colon, intestine,skin, head and neck, nerve, uterus, kidney, lung, liver, ovary,pancreas, prostate, or thyroid gland; Castleman disease; leukemia;sarcoma; lymphoma; malignoma; and melanoma; said method comprisingadministering to a subject in need thereof a therapeutic effectiveamount of a compound or a composition as defined herein.

In another embodiment, the invention provides a method for theprevention and/or treatment of kidney diseases: including but notlimited to renal fibrosis or renal dysfunction; said method comprisingadministering to a subject in need thereof a therapeutic effectiveamount of a compound or a composition as defined herein.

In another embodiment, the invention provides a method for theprevention and/or treatment of sexual dysfunction: including but notlimited to hypogonadism, bladder disease, hypertension, diabetes, orpelvic surgery; and/or to treat sexual dysfunction associated withtreatment using certain drugs, such as drugs used to treat hypertension,depression or anxiety; said method comprising administering to a subjectin need thereof a therapeutic effective amount of a compound or acomposition as defined herein.

In another embodiment, the invention provides a method for theprevention and/or treatment of blood diseases: including but not limitedto sepsis, eosinophilia, endotoxemia; said method comprisingadministering to a subject in need thereof a therapeutic effectiveamount of a compound or a composition as defined herein.

In another embodiment, the invention provides a method for theprevention and/or treatment of bone diseases: including but not limitedto osteoporosis and osteoarthritis; said method comprising administeringto a subject in need thereof a therapeutic effective amount of acompound or a composition as defined herein.

In another embodiment, the invention provides a method for theprevention and/or treatment of diabetes: including but not limited tohyperglycemia and type 1 diabetes; said method comprising administeringto a subject in need thereof a therapeutic effective amount of acompound or a composition as defined herein.

In another embodiment, the invention provides a method for theprevention and/or treatment of diseases and disorders such as benignprostatic hyperplasia, transplant rejection, liver disease, systemiclupus erythematosus, spasm, hypertension, chronic obstructive bladderdisease, premature birth, infection, allergy, obesity, pancreaticdisease and AIDS; said method comprising administering to a subject inneed thereof a therapeutic effective amount of a compound or acomposition as defined herein.

In a preferred embodiment, the invention provides a method for theprevention and/or treatment of glaucoma, asthma, sexual dysfunction orCOPD; said method comprising administering to a subject in need thereofa therapeutic effective amount of a compound or a composition as definedherein.

In the invention, particular preference is given to compounds of FormulaI or any subgroup thereof that in the inhibition assay for ROCKdescribed below inhibit ROCK with an IC₅₀ value of less than 10 μM,preferably less than 1 μM.

Said inhibition may be effected in vitro and/or in vivo, and wheneffected in vivo, is preferably effected in a selective manner, asdefined above.

The term “ROCK-mediated condition” or “disease”, as used herein, meansany disease or other deleterious condition in which is known to play arole. The term “ROCK-mediated condition” or “disease” also means thosediseases or conditions that are alleviated by treatment with a ROCKinhibitor. Accordingly, another embodiment of the present inventionrelates to treating or lessening the severity of one or more diseases inwhich ROCK is known to play a role.

For pharmaceutical use, the compounds of the invention may be used as afree acid or base, and/or in the form of a pharmaceutically acceptableacid-addition and/or base-addition salt (e.g. obtained with non-toxicorganic or inorganic acid or base), in the form of a hydrate, solvateand/or complex, and/or in the form or a pro-drug or pre-drug, such as anester. As used herein and unless otherwise stated, the term “solvate”includes any combination which may be formed by a compound of thisinvention with a suitable inorganic solvent (e.g. hydrates) or organicsolvent, such as but not limited to alcohols, ketones, esters and thelike. Such salts, hydrates, solvates, etc. and the preparation thereofwill be clear to the skilled person; reference is for instance made tothe salts, hydrates, solvates, etc. described in U.S. Pat. No.6,372,778, U.S. Pat. No. 6,369,086, U.S. Pat. No. 6,369,087 and U.S.Pat. No. 6,372,733.

The pharmaceutically acceptable salts of the compounds according to theinvention, i.e. in the form of water-, oil-soluble, or dispersibleproducts, include the conventional non-toxic salts or the quaternaryammonium salts which are formed, e.g., from inorganic or organic acidsor bases. Examples of such acid addition salts include acetate, adipate,alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,citrate, camphorate, camphorsulfonate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalene-sulfonate, nicotinate, oxalate,palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate.Base salts include ammonium salts, alkali metal salts such as sodium andpotassium salts, alkaline earth metal salts such as calcium andmagnesium salts, salts with organic bases such as dicyclohexylaminesalts, N-methyl-D-glucamine, and salts with amino acids such asarginine, lysine, and so forth. In addition, the basicnitrogen-containing groups may be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride,bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl;and diamyl sulfates, long chain halides such as decyl, lauryl, myristyland stearyl chlorides, bromides and iodides, aralkyl halides like benzyland phenethyl-bromides and others. Other pharmaceutically acceptablesalts include the sulfate salt ethanolate and sulfate salts.

Generally, for pharmaceutical use, the compounds of the inventions maybe formulated as a pharmaceutical preparation or pharmaceuticalcomposition comprising at least one compound of the invention and atleast one pharmaceutically acceptable carrier, diluent or excipientand/or adjuvant, and optionally one or more further pharmaceuticallyactive compounds.

By means of non-limiting examples, such a formulation may be in a formsuitable for oral administration, for parenteral administration (such asby intravenous, intramuscular or subcutaneous injection or intravenousinfusion), for topical administration (including ocular), foradministration by inhalation, by a skin patch, by an implant, by asuppository, etc. Such suitable administration forms—which may be solid,semi-solid or liquid, depending on the manner of administration—as wellas methods and carriers, diluents and excipients for use in thepreparation thereof, will be clear to the skilled person; reference isagain made to for instance U.S. Pat. No. 6,372,778, U.S. Pat. No.6,369,086, U.S. Pat. No. 6,369,087 and U.S. Pat. No. 6,372,733, as wellas to the standard handbooks, such as the latest edition of Remington'sPharmaceutical Sciences.

Some preferred, but non-limiting examples of such preparations includetablets, pills, powders, lozenges, sachets, cachets, elixirs,suspensions, emulsions, solutions, syrups, aerosols, ointments, creams,lotions, soft and hard gelatin capsules, suppositories, eye drops,sterile injectable solutions and sterile packaged powders (which areusually reconstituted prior to use) for administration as a bolus and/orfor continuous administration, which may be formulated with carriers,excipients, and diluents that are suitable per se for such formulations,such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gumacacia, calcium phosphate, alginates, tragacanth, gelatin, calciumsilicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethyleneglycol, cellulose, (sterile) water, methylcellulose, methyl- andpropylhydroxybenzoates, talc, magnesium stearate, edible oils, vegetableoils and mineral oils or suitable mixtures thereof. The formulations canoptionally contain other pharmaceutically active substances (which mayor may not lead to a synergistic effect with the compounds of theinvention) and other substances that are commonly used in pharmaceuticalformulations, such as lubricating agents, wetting agents, emulsifyingand suspending agents, dispersing agents, desintegrants, bulking agents,fillers, preserving agents, sweetening agents, flavoring agents, flowregulators, release agents, etc. The compositions may also be formulatedso as to provide rapid, sustained or delayed release of the activecompound(s) contained therein, for example using liposomes orhydrophilic polymeric matrices based on natural gels or syntheticpolymers. In order to enhance the solubility and/or the stability of thecompounds of a pharmaceutical composition according to the invention, itcan be advantageous to employ α-, β- or γ-cyclodextrins or theirderivatives. An interesting way of formulating the compounds incombination with a cyclodextrin or a derivative thereof has beendescribed in EP-A-721,331. In particular, the present inventionencompasses a pharmaceutical composition comprising an effective amountof a compound according to the invention with a pharmaceuticallyacceptable cyclodextrin.

In addition, co-solvents such as alcohols may improve the solubilityand/or the stability of the compounds. In the preparation of aqueouscompositions, addition of salts of the compounds of the invention can bemore suitable due to their increased water solubility.

Particular reference is made to the compositions, formulations (andcarriers, excipients, diluents, etc. for use therein), routes ofadministration etc., which are known per se for analogouspyridinocarboxamides, such as those described in U.S. Pat. No. 4,997,834and EP-A-0 370 498.

For the treatment of pain, the compounds of the invention may be usedlocally. For local administration, the compounds may advantageously beused in the form of a spray, ointment or transdermal patch or anothersuitable form for topical, transdermal and/or intradermaladministration.

For ophthalmic application, solutions, gels, tablets and the like areoften prepared using a physiological saline solution, gel or excipientas a major vehicle. Ophthalmic formulations should preferably beprepared at a comfortable pH with an appropriate buffer system.

More in particular, the compositions may be formulated in apharmaceutical formulation comprising a therapeutically effective amountof particles consisting of a solid dispersion of the compounds of theinvention and one or more pharmaceutically acceptable water-solublepolymers.

The term “a solid dispersion” defines a system in a solid state (asopposed to a liquid or gaseous state) comprising at least twocomponents, wherein one component is dispersed more or less evenlythroughout the other component or components. When said dispersion ofthe components is such that the system is chemically and physicallyuniform or homogenous throughout or consists of one phase as defined inthermodynamics, such a solid dispersion is referred to as “a solidsolution”. Solid solutions are preferred physical systems because thecomponents therein are usually readily bioavailable to the organisms towhich they are administered.

It may further be convenient to formulate the compounds in the form ofnanoparticles which have a surface modifier adsorbed on the surfacethereof in an amount sufficient to maintain an effective averageparticle size of less than 1000 nm. Suitable surface modifiers canpreferably be selected from known organic and inorganic pharmaceuticalexcipients. Such excipients include various polymers, low molecularweight oligomers, natural products and surfactants. Preferred surfacemodifiers include nonionic and anionic surfactants.

Yet another interesting way of formulating the compounds according tothe invention involves a pharmaceutical composition whereby thecompounds are incorporated in hydrophilic polymers and applying thismixture as a coat film over many small beads, thus yielding acomposition with good bio-availability which can conveniently bemanufactured and which is suitable for preparing pharmaceutical dosageforms for oral administration. Materials suitable for use as cores inthe beads are manifold, provided that said materials arepharmaceutically acceptable and have appropriate dimensions andfirmness. Examples of such materials are polymers, inorganic substances,organic substances, and saccharides and derivatives thereof.

The preparations may be prepared in a manner known per se, which usuallyinvolves mixing at least one compound according to the invention withthe one or more pharmaceutically acceptable carriers, and, if desired,in combination with other pharmaceutical active compounds, whennecessary under aseptic conditions. Reference is again made to U.S. Pat.No. 6,372,778, U.S. Pat. No. 6,369,086, U.S. Pat. No. 6,369,087 and U.S.Pat. No. 6,372,733 and the further prior art mentioned above, as well asto the standard handbooks, such as the latest edition of Remington'sPharmaceutical Sciences.

The pharmaceutical preparations of the invention are preferably in aunit dosage form, and may be suitably packaged, for example in a box,blister, vial, bottle, sachet, ampoule or in any other suitablesingle-dose or multi-dose holder or container (which may be properlylabeled); optionally with one or more leaflets containing productinformation and/or instructions for use. Generally, such unit dosageswill contain between 1 and 1000 mg, and usually between 5 and 500 mg, ofthe at least one compound of the invention, e.g. about 10, 25, 50, 100,200, 300 or 400 mg per unit dosage.

The compounds can be administered by a variety of routes including theoral, rectal, ocular, transdermal, subcutaneous, intravenous,intramuscular or intranasal routes, depending mainly on the specificpreparation used and the condition to be treated or prevented, and withoral and intravenous administration usually being preferred. The atleast one compound of the invention will generally be administered in an“effective amount”, by which is meant any amount of a compound of theFormula I-XXIV or any subgroup thereof that, upon suitableadministration, is sufficient to achieve the desired therapeutic orprophylactic effect in the individual to which it is administered.Usually, depending on the condition to be prevented or treated and theroute of administration, such an effective amount will usually bebetween 0.01 to 1000 mg per kilogram body weight day of the patient perday, more often between 0.1 and 500 mg, such as between 1 and 250 mg,for example about 5, 10, 20, 50, 100, 150, 200 or 250 mg, per kilogrambody weight day of the patient per day, which may be administered as asingle daily dose, divided over one or more daily doses, or essentiallycontinuously, e.g. using a drip infusion. The amount(s) to beadministered, the route of administration and the further treatmentregimen may be determined by the treating clinician, depending onfactors such as the age, gender and general condition of the patient andthe nature and severity of the disease/symptoms to be treated. Referenceis again made to U.S. Pat. No. 6,372,778,U.S. Pat. No. 6,369,086, U.S.Pat. No. 6,369,087 and U.S. Pat. No. 6,372,733 and the further prior artmentioned above, as well as to the standard handbooks, such as thelatest edition of Remington's Pharmaceutical Sciences.

In accordance with the method of the present invention, saidpharmaceutical composition can be administered separately at differenttimes during the course of therapy or concurrently in divided or singlecombination forms. The present invention is therefore to be understoodas embracing all such regimes of simultaneous or alternating treatmentand the term “administering” is to be interpreted accordingly.

For an oral administration form, the compositions of the presentinvention can be mixed with suitable additives, such as excipients,stabilizers, or inert diluents, and brought by means of the customarymethods into the suitable administration forms, such as tablets, coatedtablets, hard capsules, aqueous, alcoholic, or oily solutions. Examplesof suitable inert carriers are gum arabic, magnesia, magnesiumcarbonate, potassium phosphate, lactose, glucose, or starch, inparticular, corn starch. In this case, the preparation can be carriedout both as dry and as moist granules. Suitable oily excipients orsolvents are vegetable or animal oils, such as sunflower oil or codliver oil. Suitable solvents for aqueous or alcoholic solutions arewater, ethanol, sugar solutions, or mixtures thereof. Polyethyleneglycols and polypropylene glycols are also useful as further auxiliariesfor other administration forms. As immediate release tablets, thesecompositions may contain microcrystalline cellulose, dicalciumphosphate, starch, magnesium stearate and lactose and/or otherexcipients, binders, extenders, disintegrants, diluents and lubricantsknown in the art.

When administered by nasal aerosol or inhalation, these compositions maybe prepared according to techniques well-known in the art ofpharmaceutical formulation and may be prepared as solutions in saline,employing benzyl alcohol or other suitable preservatives, absorptionpromoters to enhance bioavailability, fluorocarbons, and/or othersolubilizing or dispersing agents known in the art. Suitablepharmaceutical formulations for administration in the form of aerosolsor sprays are, for example, solutions, suspensions or emulsions of thecompounds of the invention or their physiologically tolerable salts in apharmaceutically acceptable solvent, such as ethanol or water, or amixture of such solvents. If required, the formulation can alsoadditionally contain other pharmaceutical auxiliaries such assurfactants, emulsifiers and stabilizers as well as a propellant.

For subcutaneous administration, the compound according to theinvention, if desired with the substances customary therefore such assolubilizers, emulsifiers or further auxiliaries are brought intosolution, suspension, or emulsion. The compounds of the invention canalso be lyophilized and the lyophilizates obtained used, for example,for the production of injection or infusion preparations. Suitablesolvents are, for example, water, physiological saline solution oralcohols, e.g. ethanol, propanol, glycerol, in addition also sugarsolutions such as glucose or mannitol solutions, or alternativelymixtures of the various solvents mentioned. The injectable solutions orsuspensions may be formulated according to known art, using suitablenon-toxic, parenterally-acceptable diluents or solvents, such asmannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodiumchloride solution, or suitable dispersing or wetting and suspendingagents, such as sterile, bland, fixed oils, including synthetic mono- ordiglycerides, and fatty acids, including oleic acid.

When rectally administered in the form of suppositories, theseformulations may be prepared by mixing the compounds according to theinvention with a suitable non-irritating excipient, such as cocoabutter, synthetic glyceride esters or polyethylene glycols, which aresolid at ordinary temperatures, but liquefy and/or dissolve in therectal cavity to release the drug.

In preferred embodiments, the compounds and compositions of theinvention are used locally, for instance topical or in both absorbed andnon-adsorbed applications.

The compositions are of value in the veterinary field, which for thepurposes herein not only includes the prevention and/or treatment ofdiseases in animals, but also—for economically important animals such ascattle, pigs, sheep, chicken, fish, etc.—enhancing the growth and/orweight of the animal and/or the amount and/or the quality of the meat orother products obtained from the animal. Thus, in a further aspect, theinvention relates to a composition for veterinary use that contains atleast one compound of the invention and at least one suitable carrier(i.e. a carrier suitable for veterinary use). The invention also relatesto the use of a compound of the invention in the preparation of such acomposition.

The invention will now be illustrated by means of the followingsynthetic and biological examples, which do not limit the scope of theinvention in any way.

EXAMPLES A. Physicochemical Properties of the Compounds

A.1. Compound Purity

Unless indicated otherwise, the purity of the compounds was confirmed byliquid chromatography/mass spectrometry (LC/MS), as follows:

HPLC system: Waters 2690 with photodiode array detector Waters 996;Column: C18; Gradient: solvent A (H₂O/formic acid 26.5 nM) 0%, tosolvent B (CH₃CN/formic acid 17 nM) 80% in 3 min. Flow: 2.75 ml/min.

Mass spectrometer: Micromass Platform LC. Ionization: electrospray(polarity: negative and positive).

A.2. Attribution of the Configuration:

The Cahn-Ingold-Prelog system was used to attribute the absoluteconfiguration of chiral center, in which the four groups on anasymmetric carbon are ranked to a set of sequences rules. Reference ismade to Cahn; Ingold; Prelog Angew. Chem. Int. Ed. Engl. 1966, 5,385-415.

A.3. Stereochemistry:

It is known by those skilled in the art that specific enantiomers (ordiastereoisomers) can be obtained by different methods such as, but notlimited to chiral resolution (for example, salts formed with opticallyactive acids or bases may be used to form diastereoisomeric salts thatcan facilitate the separation of optically active isomers of thecompounds of Formula I or any subgroup thereof), assymetric synthesis orpreparative chiral chromatography (using different column such asChiralcel OD-H (tris-3,5-dimethylphenylcarbamate, 46×250 or 100×250 mm,5 μm), Chiralcel OJ (tris-methylbenzoate, 46×250 or 100×250 mm, 5 μm),Chiralpak AD (tris-3,5-dimethylphenylcarbamate, 46×250 mm, 10 μm) andChiralpak AS (tris-(S)-1-phenylethylcarbamate, 46×250 mm, 10 μm) fromChiral Technologies Europe (Illkirch, France)). Whenever it isconvenient, stereoisomers can be obtained starting from commercialmaterials with known configuration (such compounds include aminoacid forinstance).

A.4. Name of the Molecules

The software MDL ISIS™/Draw 2.3 was used to assign the name of themolecules.

B. Compound Synthesis

B.1. Intermediates

The compounds of the invention may be prepared by methods well known tothose skilled in the art, and as described in the synthetic andexperimental procedures shown below.

For example, intermediates C can be obtained according to, but notlimited to the following general sequence (amide formation followed bysuzuki coupling):

PG represents a suitable protecting group such as groups described by T.Greene and P. Wuts, in “Greene's Protective Group in Organic Chemistry”(4th edition, John Wiley & Sons Inc).

General Procedures for Preparation of Amides

Protocol A.

To a solution of the corresponding carboxylic acid (1 mmol) in DMF (10ml) were added DIEA (3 mmol, 3 eq.), TBTU (1.3 mmol, 1.3 eq.) and HOBt(0.3 mmol, 0.3 eq.). The reaction mixture was stirred at rt for 5-10 minfollowed by addition of the corresponding amine (1.1 eq.). The reactionmixture was stirred for 16 to 24 hours, then diluted with ethyl acetate(100 mL), washed with 0.1 M HCl (50 mL) and saturated sodium carbonate(50 mL). The organic phase was dried over MgSO₄ and the solvent wasremoved in vacuo.

Alternative protocol: To a solution of the corresponding carboxylic acid(1 eq) in a mixture DMF/DCM (0.25 M) were successively added DCC (1 eq),HOBt (1 eq) and DIEA (3 eq). The solution was stirred at RT for 30minutes before the addition of the corresponding amine (1 eq). Thereaction mixture was stirred at RT for 1 hour to 3 days. The solventremoved in vacuo. The residue was partitioned between DCM and water. Theproduct was extracted with DCM. The organic layer was separated, washedwith 2M sodium carbonate (or 1N NaOH), 1N HCl, brine, dried over MgSO₄,and evaporated.

Alternative protocol: A mixture of the corresponding carboxylic acid(200 mg, 1.0 eq) and amine (2.0 eq) in CH₃CN (4 ml) was added HOBT (0.4eq) and EDCI (about 120 mg, 1.5 eq). The reaction mixture was stirred at30° C. for 16 hrs. LC-MS showed the reaction was complete. Then thesolvent was concentrated to dryness to give crude product, which wasused directly for next step without purification.

The crude product was dissolved in DCM/TFA=7:1 (4 ml). The reactionmixture was stirred at 30° C. for 16 hrs. LC-MS showed the reaction wascomplete. Then the reaction mixture was concentrated and the crudeproduct was purified by prep HPLC to give the final product.

Protocol B.

To a solution of the corresponding carboxylic acid (5 mmol) in dry THF(10 ml) was added Ghosez reagent (10 mmol, 2 eq.). The reaction mixturewas stirred at rt for 2.5 hours and the solvent was removed in vacuo.The residue was dissolved in dry pyridine and cooled to 0° C. followedby addition of the corresponding amine (5.5 mmol, 1.1 eq.). The reactionmixture was stirred at rt for 1 hour. The pyridine was removed byco-evaporation with toluene, the residue was dissolved in EtOAc (100 mL)and washed with 1M NaOH (50 mL), water (50 mL) and brine (50 mL). Theorganic phase was dried over MgSO₄ and the solvent was removed in vacuo

Protocol C.

A solution of the corresponding carboxylic acid (1 mmol) in dioxane (2ml) was degassed by bubbling nitrogen through the solution. Copper(I)-iodide (0.25 mmol, 0.25 eq), Cs₂CO₃ (2.5 mmol, 2.5 eq.), thecorresponding amine (1.2 mmol, 1.2 eq.) andN,N′-dimethyl-ethane-1,2-diamine (0.5 mmol, 0.5 eq.) were added. Thereaction mixture was stirred in a closed vial at 130° C. for 24 hours.The reaction mixture was filtered over Celite and the Celite was washedwith EtOAc (200 mL). The filtrate was washed with 1M sodium bicarbonate(100 mL), 0.1M HCl (100 mL), water (100 mL) and brine (100 mL). Theorganic layer was dried over MgSO₄ and the solvent was removed in vacuo.

Protocol D. General Procedure for Suzuki Reaction

A MW vessel (Biotage, 20 mL) was charged with an appropriate boronicacid (3 mmol, 2 eq), the corresponding phenyl bromide (1.5 mmol, 1 eq),toluene or DME (3 mL), ethanol (3 mL) and 2M sodium carbonate solution(3 mL, 6 mmol, 4 eq). The reaction vessel was then flushed with nitrogenbefore adding tetrakis(triphenyl phosphine) palladium (0) catalyst (4mol %). The reaction vessel was again flushed with nitrogen beforesealing and irradiating in MW at 130° C. for 1-1.5 h. The reactionmixture residue was then cooled down and filtered through Celite. Theresidue was washed with ethyl acetate (200 mL) and methanol (100 mL) Thesolvent was removed in vacuo and the residue was taken up in DCM. Theprecipitate was filtered, washed with DCM and dried. The compound wasused as such or was purified by flash chromatography (silicagel,DCM/MeOH gradient).

Intermediate 1: 3-Bromo-4-(1-tert-butoxycarbonylamino-ethyl)-benzoicacid

To a solution of 4-acetyl-3-bromo-benzoic acid (40 to 80 mmol) in EtOH(100 to 200 ml) was added DIEA (1.6 eq.) and hydroxylamine hydrochloride(1.6 eq.). The reaction mixture was stirred under reflux conditions for1 hour. The reaction mixture was cooled to room temperature and thesolvent was removed under reduced pressure. The residue was taken up inwater and a 20% KHSO₄ solution. The precipitate was filtered, washedwith water and dried.

To a solution of 3-bromo-4-[1-(hydroximino)-ethyl]-benzoic acid (10 to50 mmol) in acetic acid (30 to 300 ml) was added activated zinc (5 to 10eq.). The reaction mixture was stirred at room temperature for 10minutes or up to 3.5 hours. The reaction mixture was filtered and theprecipitate was washed with acetic acid. The solvent of the filtrate wasremoved under reduced pressure.

The crude 4-(1-amino-ethyl)-3-bromo-benzoic acid (15323 to 30727 μmol)was suspended in a mixture of THF/1M Na₂CO₃: 1/1 (100 ml) or a mixtureof acetone/1M Na₂CO₃: 1/1 (100 ml) or a mixture of acetone/2M Na₂CO₃:8/2 (100 ml) and (Boc)₂O (1.5 eq) was added. The reaction mixture wasstirred at RT for 1 to 2 hours. The organic solvent was removed underreduced pressure or diethylether was added and the two layers wereseparated or the reaction mixture was filtered and the organic solventwas removed under reduced pressure. The aqueous residue was diluted withcitric acid or with a 20% KHSO₄ solution and extracted with EtOAc. Thecombined organic layers were washed with brine, dried over MgSO₄ and thesolvent was removed under reduced pressure. The compound was when neededpurified by column chromatography (silicagel, DCM/MeOH gradient).

Intermediate 2:{1-[2-Bromo-4-(pyridine-4-ylcarbamoyl)-phenyl]-ethyl}-carbamic acidtert-butyl ester

To a solution of 3-bromo-4-(1-tert-butoxycarbonylamino-ethyl)-benzoicacid (7496 to 61011 μmol) in DMF (10 to 30 ml) were added DIEA (2 eq.),TBTU (1.3 eq.) and HOBt (0.3 eq.). The reaction mixture was stirred atRT for 5 minutes. 4-Aminopyridine (1.5 eq) was added and the reactionmixture was stirred at RT for 2.5 hours up to overnight. When there wasstill starting material observed, more DIEA (0.39 eq), TBTU (0.25 eq),HOBt (0.06 eq) and 4-aminopyridine (0.28 eq) were added and the reactionmixture was stirred at RT for another 2 hours. The reaction mixture wasdiluted with EtOAc, washed with 0.1 M HCl and saturated Na₂CO₃ or withsaturated NaHCO₃. The organic layer was dried over MgSO₄ and the solventwas removed under reduced pressure. The compound was purified by columnchromatography (silicagel, DCM/MeOH gradient).

Intermediate 3:2′-(1-tert-Butoxycarbonylamino-ethyl)-5′-(pyridin-4-ylcarbamoyl)-biphenyl-3-carboxylicacid

Method 1: To a solution of{1-[2-bromo-4-(pyridine-4-yl-carbamoyl)-phenyl]-ethyl}-carbamic acidtert-butyl ester (2 to 3 mmol) and 3-carboxyphenylboronic acid (1.2 eq.)in a mixture of DME/EtOH/water: 2/1/1 (10 ml) was added Na₂CO₃ (4 eq)and Pd tetrakis (0.05 eq). The reaction mixture was heated in themicrowave at 135° C. for 30 min. The solvents were removed under reducedpressure. The residue was diluted with MeOH and filtered over celite.The celite residue was washed with MeOH. The solvent was removed underreduced pressure and the residue was taken up in DCM. The precipitatewas filtered, washed with DCM and dried. The compound was purified bysemi-preparative LC-MS. Or the residue was diluted with DCM/MeOH (3/2)and activated charcoal was added to the reaction mixture. The mixturewas stirred at RT for 10 minutes and filtered over silicagel. Theresidue was washed with DCM/MeOH (8/2) followed by MeOH. The solvent wasthen removed under reduced pressure.

Method 2: To a solution of{1-[2-bromo-4-(pyridine-4-yl-carbamoyl)-phenyl]-ethyl}-carbamic acidtert-butyl ester (6912 μmol) and 3-carboxyphenylboronic acid (1.0 eq.)in a mixture of toluene/EtOH: 5/3 (32 ml) was added a solution of Na₂CO₃(3 eq) in water (8 ml) and Pd tetrakis (0.03 eq). The reaction mixturewas heated under reflux conditions for 3 hours. More3-carboxyphenylboronic acid (0.35 eq.) and Pd tetrakis (0.015 eq) wereadded and the mixture was again heated under reflux conditions for 3hours. The reaction mixture was cooled to RT and filtered over celite.The celite residue was washed with EtOAc and MeOH. The solvents wereremoved under reduced pressure and the compound was purified by columnchromatography (silicagel, DCM/MeOH gradient).

Intermediate 4:[2′-(1-tert-Butoxycarbonylamino-ethyl)-5′-(pyridin-4-ylcarbamoyl)-biphenyl-3-yl]-aceticacid

To a solution of{1-[2-bromo-4-(pyridine-4-ylcarbamoyl)-phenyl]-ethyl}-carbamic acidtert-butyl ester (1951 μmol) in a mixture of DME/EtOH/2N Na₂CO₃: 1/1/1(10 ml) were added 3-carboxymethylphenylboronic acid (1.5 eq) and Pdtetrakis (0.05 eq). The reaction mixture was heated in the microwave at160° C. for 15 minutes. The reaction mixture was cooled to RT, filteredover celite and washed with EtOAc and MeOH. The solvents were removedunder reduced pressure. The compound was purified by columnchromatography (silicagel, DCM/MeOH gradient).

Intermediate 5:3-[2′-(1-tert-Butoxycarbonylamino-ethyl)-5′-(pyridin-4-ylcarbamoyl)-biphenyl-3-yl]-propionicacid

To a solution of{1-[2-bromo-4-(pyridine-4-ylcarbamoyl)-phenyl]-ethyl}-carbamic acidtert-butyl ester (3122 μmol) in a mixture of DME/EtOH/2N Na₂CO₃: 1/1/1(20 ml) were added 3-carboxyethylphenylboronic acid (1.5 eq) and Pdtetrakis (0.05 eq). The reaction mixture was heated in the microwave at160° C. for 15 minutes. The reaction mixture was cooled to RT, filteredover celite and washed with EtOAc and MeOH. The solvents were removedunder reduced pressure. The compound was purified by columnchromatography (silicagel, DCM/MeOH gradient).

Intermediate 6:{1-[3′-Hydroxy-5-(pyridin-4-ylcarbamoyl)-biphenyl-2-yl]-ethyl}-carbamicacid tert-butyl ester

To a solution of{1-[2-bromo-4-(pyridine-4-ylcarbamoyl)-phenyl]-ethyl}-carbamic acidtert-butyl ester (2087 μmol) and 3-hydroxyphenylboronic acid (1.55 eq)in a mixture of DME/EtOH: 1/1 (8 ml) were added Na₂CO₃ (4 eq) and Pdtetrakis (0.05 eq.). The reaction mixture was flushed with Ar and washeated in the microwave at 130° C. for 1.5 hours. The reaction mixturewas cooled to RT, diluted with 1N NaHCO₃ and extracted with EtOAc. Theorganic layer was extracted with 1N NaHCO₃ and the combined aqueouslayers were acidified with citric acid and 1N HCl. The aqueous layer wasextracted with EtOAc, the organic layer was dried over MgSO₄ and thesolvent was removed under reduced pressure. The compound was purified byrecrystallization from EtOAc.

Intermediate 7:[2′-(1-tert-Butoxycarbonylamino-ethyl)-5′-(pyridin-4-ylcarbamoyl)-biphenyl-3-yloxy]-aceticacid

To a solution of{1-[2-Bromo-4-(pyridine-4-ylcarbamoyl)-phenyl]-ethyl}-carbamic acidtert-butyl ester (0.48 g) in a mixture of toluene/ethanol: 5/3 (12 ml)were added 3-phenoxy-acetic acid benzyl ester boronic acid (2 eq.), asolution of Na₂CO₃ (4 eq.) in water (4 ml) and Pd tetrakis (0.06 eq.).The reaction mixture was heated under reflux conditions for 2 hours. Thereaction mixture was cooled to RT and filtered over celite. The celiteresidue was washed with EtOAc and EtOH. The solvent was removed underreduced pressure and the residue was taken up in DCM. The precipitatewas filtered, washed with DCM and dried. The compound was purified bycolumn chromatography (silicagel, DCM/MeOH gradient).

Intermediate 8:{1-[2-Bromo-4-(3-fluoro-pyridine-4-ylcarbamoyl)-phenyl]-ethyl}-carbamicacid tert-butyl ester

To a solution of 3-bromo-4-(1-tert-butoxycarbonylamino-ethyl)-benzoicacid (8352 μmol) in dry THF (20 ml) was added Ghosez reagent (2 eq.).The mixture was stirred at RT for 2 hours. The solvent was removed underreduced pressure. The residue was dissolved in dry pyridine (20 ml) and3-fluoro-pyridin-4-ylamine (1.2 eq) was added. The reaction mixture wasstirred at RT for 2.5 hours. The pyridine was removed under reducedpressure. The residue was dissolved in 1N Na₂CO₃ and extracted withEtOAc. The combined organic layers were washed with 1N NaHCO₃, citricacid and water. The organic layer was dried over MgSO₄ and the solventwas removed under reduced pressure. The compound was purified by columnchromatography (silicagel, DCM/MeOH gradient).

Intermediate 9:2′-(1-tert-Butoxycarbonylamino-ethyl)-5′-(3-fluoro-pyridin-4-ylcarbamoyl)-biphenyl-3-carboxylicacid

To a solution of{1-[2-bromo-4-(3-fluoro-pyridin-4-ylcarbamoyl)-phenyl]-ethyl}-carbamicacid tert-butyl ester (2841 μmol) and 3-carboxyphenylboronic acid (1.5eq.) in a mixture of DME/EtOH/water: 1/1/1 (10 ml) was added Na₂CO₃ (4eq) and Pd tetrakis (0.05 eq). The reaction mixture was heated in themicrowave at 130° C. for 15 hours. The reaction mixture was diluted withwater and citric acid (to acidic pH) and extracted with EtOAc. Thecombined organic layers were dried over MgSO₄ and the solvent wasremoved under reduced pressure. The compound was purified by columnchromatography (silicagel, DCM/MeOH gradient).

Intermediate 10:[2′-(1-tert-Butoxycarbonylamino-ethyl)-5′-(3-fluoro-pyridin-4-ylcarbamoyl)-biphenyl-3-yloxy]-aceticacid

To a solution of{1-[2-bromo-4-(3-fluoro-pyridin-4-ylcarbamoyl)-phenyl]-ethyl}-carbamicacid tert-butyl ester (3400 to 3650 μmol) and the 3-phenoxy-acetic acidbenzyl ester boronic acid (1 eq) in DMEwater: 9/1 (15 ml) were addedK₃PO₄ (4 eq.) and Pd tetrakis (0.05 eq.). The reaction mixture washeated in the microwave at 130° C. for 30 minutes. Activated charcoalwas added to the reaction mixture and the mixture was filtered overcelite. The residue was washed with EtOAc and water. The aqueous layerwas separated and extracted with EtOAc. The combined organic layers werewashed with brine, dried over MgSO₄ and the solvent was removed underreduced pressure. The compound was purified by column chromatography(silicagel, cyclohexane/acetone gradient).

To a solution of[2′-(1-tert-butoxycarbonylamino-ethyl)-5′-(3-fluoro-pyridin-4-ylcarbamoyl)-phenyl]-biphenyl-3-yloxy]-aceticacid benzyl ester (2 mmol) in THF (25 ml) was added Pd/C (0.5 eq). Thereaction mixture was flushed with hydrogen. A solution of cyclohexadienein THF (5 ml) was added dropwise to the reaction mixture. The mixturewas stirred at 55° C. for 24 hours under hydrogen atmosphere. Celite wasadded and the suspension was stirred at RT for 20 minutes. Thesuspension was filtered and the residue was washed with THF (50 ml). Thesolvent was removed under reduced pressure.

Intermediate 11:{1-[3′-Amino-5-(pyridin-4-ylcarbamoyl)-biphenyl-2-yl]-ethyl}-carbamicacid tert-butyl ester

To a solution of{1-[b-bromo-4-(pyridine-4-ylcarbamoyl)-phenyl]-ethyl}-carbamic acidtert-butyl ester (1428 μmol) and 3-aminophenylboronic acid (2 eq) in amixture of DME/ethanol/1N Na₂CO₃: 1/1/1 (3 ml) was added Pd tetrakis(0.05 eq). The reaction mixture was heated in the microwave at 150° C.for 15 minutes. The reaction mixture was cooled to RT and diluted withwater and extracted with EtOAc. The combined organic layers were washedwith 0.5N HCl, dried over MgSO₄ and the solvent was removed underreduced pressure.

Intermediate 12:{1-[3′-Amino-5-(3-fluoro-pyridin-4-ylcarbamoyl)-biphenyl-2-yl]-ethyl}-carbamicacid tert-butyl ester

To a solution of{1-[2-bromo-4-(3-fluoro-pyridine-4-ylcarbamoyl)-phenyl]-ethyl}-carbamicacid tert-butyl ester (1094 μmol) and 3-aminophenylboronic acid (2 eq)in a mixture of DME/ethanol/1N Na₂CO₃: 1/1/1 (10 ml) was added Pdtetrakis (0.05 eq). The reaction mixture was heated in the microwave at130° C. for 1.5 hours. The reaction mixture was cooled to RT and dilutedwith water and citric acid and extracted with EtOAc. The combinedorganic layers were washed with water and brine. The organic layer wasdried over MgSO₄ and the solvent was removed under reduced pressure. Thecompound was purified by column chromatography (silicagel, DCM/MeOHgradient).

Intermediate 13:4-[2-(1-tert-Butoxycarbonylamino-ethyl)-5-(pyridin-4-ylcarbamoyl)-phenyl]-1H-pyrrole-2-carboxylicacid

To a solution of{1-[2-bromo-4-(pyridine-4-ylcarbamoyl)-phenyl]-ethyl}-carbamic acidtert-butyl ester (809 μmol) and 1H-pyrrole-2-carboxylic acid methylester boronic acid (1.15 eq) in a mixture of DME/EtOH: 1/1 (0.8 ml) wereadded Na₂CO₃ (4 eq) and Pd tetrakis (0.05 eq.). The reaction mixture wasflushed with Ar and was heated in the microwave at 130° C. for 35minutes. The reaction mixture was cooled to RT, diluted with water andextracted with EtOAc. The solvent of the organic layer was removed underreduced pressure.

To a solution of4-[2-(1-tert-Butoxycarbonylamino-ethyl)-5-(pyridin-4-ylcarbamoyl)-phenyl]-1H-pyrrole-2-carboxylicacid methyl ester (661 μmol) in THF (1.6 ml) and MeOH (1.6 ml) was addeda 1N LiOH solution (1.6 ml). The reaction mixture was stirred at 40° C.for 1.5 hours. The reaction mixture was diluted with saturated NaHCO₃and extracted with EtOAc. The aqueous layer is acidified with a 20%citric acid solution and extracted again with EtOAc. The combinedorganic layers were dried over MgSO₄ and the solvent was removed underreduced pressure.

Intermediate 14:4-[2-(1-tert-Butoxycarbonylamino-ethyl)-5-(pyridin-4-ylcarbamoyl)-phenyl]-1H-indole-2-carboxylicacid

To a solution of{1-[2-bromo-4-(pyridine-4-ylcarbamoyl)-phenyl]-ethyl}-carbamic acidtert-butyl ester (952 μmol) and 4-bromo-1H-indole-2-carboxylic acidmethyl ester boronic acid (1.55 eq) in a mixture of DME/EtOH: 1/1 (8 ml)were added Na₂CO₃ (4 eq) and Pd tetrakis (0.05 eq.). The reactionmixture was flushed with Ar and was heated in the microwave at 130° C.for 35 minutes. The reaction mixture was cooled to RT, diluted withwater and filtered. The residue was dried.

To a solution of4-[2-(1-amino-ethyl)-5-(pyridin-4-ylcarbamoyl)-phenyl]-1H-indole-2-carboxylicacid methyl ester (600 μmol) in THF (2.4 ml) and MeOH (2.4 ml) was addeda 1N LiOH solution (2.4 ml). The reaction mixture was stirred at 40° C.for 6 hours. The reaction mixture was diluted with 1N LiOH and extractedwith EtOAc. The aqueous layer is acidified with a 20% citric acidsolution and extracted again with EtOAc. The combined organic layerswere dried over MgSO₄ and the solvent was removed under reducedpressure.

Intermediate 15: 3-Bromo-4-(tert-butoxycarbonylamino-methyl)-benzoicacid

To a suspension of 3-Bromo-4-methylbenzoic acid (300 g, 1.39 mol) inMeOH (3 L) was added H₂SO₄ (6 ml). The reaction mixture was stirred at60° C. overnight. The reaction was cooled to room temperature,evaporated and the residue was dissolved in EtOAc (2 L), The EtOAcsolution was washed with saturated NaHCO₃ (1 L), dried over MgSO₄ andconcentrated to dryness to give the corresponding methyl ester as paleyellow oil (303 g, 95% yield).

A solution of the previous methyl ester (303 g, 0.98 mol, 1.0 eq) inanhydrous CCl₄ (1.5 L) was added to a solution of NBS (183.9 g, 1.03mol, 1.05 eq) and AIBN (8 g, 0.049 mol, 0.05 eq) in anhydrous CCl₄ (1.5L) at room temperature. The reaction mixture was refluxed for 16 hrs,cooled to room temperature, evaporated and the residue was dissolved inDCM (2.5 L). The DCM solution was washed with saturated NaHCO₃ (0.6 L),and H₂O (1 L*3). The organic layer was dried over MgSO₄ and concentratedto dryness to give crude 3-bromo-4-bromomethyl-benzoic acid methyl esterwhich was used for next step without further purification.

Boc₂NH (175 g, 0.925 mol, 1.0 eq) was added to a solution of t-BuOK(124.5 g, 1.11 mol 1.02 eq) in DMF (3 L), the resulting solution wasstirred for 1 h at room temperature. Crude 3-bromo-4-bromomethyl-benzoicacid methyl ester was added to above reaction solution at roomtemperature and stirred overnight. The solvent was removed under vacuumand the residue was dissolved in DCM (500 ml). The DCM solution waswashed with water (3×500 ml), dried over MgSO₄ and concentrated. Thecrude product was purified by column chromatography on silica gel usingPE:EA=20:1 to give diBoc-4-Aminomethyl-3-bromo-benzoic acid methyl ester(290 g, 70% yield) as yellow solid

To a solution of the previous di_Boc protected benzylamine (290 g, 0.652mol, 1.0 eq) in DCM (2.9 L) was added TFA (92.8 g, 0.813 mol, 1.25 eq)dropwise at 0° C., the resulting mixture was stirred at room temperaturefor 4 hrs. 0.5 M NaHCO₃ was added to the mixture to adjust pH to 8. Thereaction mixture was washed with water (3*500 ml), dried over MgSO₄ andconcentrated by rotavapor to give3-bromo-4-(tert-butoxycarbonylamino-methyl)-benzoic acid methyl ester(210 g, 93.5% yield) as yellow oil.

NaOH (48.8 g, 1.22 mol, 2.0 eq) in H₂O (1.26 L) was added to a solutionof 3-bromo-4-(tert-butoxycarbonylamino-methyl)-benzoic acid methyl ester(210 g, 0.61 mol, 1.0 eq) in MeOH (1.26 L). The reaction mixture wasstirred at 50° C. for 2 hrs. The reaction was cooled to room temperatureand concentrated to half volume. The residue was acidified to pH 5 byadding 1M HCl solution. The resulting solid was collected and dried togive the title intermediate (200 g, 99.4% yield) as white solid.

Intermediate 16: [2-Bromo-4-(pyridin-4-ylcarbamoyl)-benzyl]-carbamicacid tert-butyl ester

To a solution of Intermediate 15 (100 g, 0.303 mol, 1.0 eq) and4-aminopyridine (28.5 g, 0.303 mol, 1.0 eq) in DMA (1 L) was added Et₃N(30.6 g, 0.303 mol, 1.0 eq), DMAP (3.7 g, 0.030 mol, 0.1 eq) and HATU(115.2 g, 0.303 mol, 1.0 eq). The reaction solution was stirred at 30°C. for 16 hrs. Solvent was evaporated under vacuum and the residue wassolidified by adding DCM (600 ml) and H₂O (600 ml) to give the titlecompound (86.1 g, 70% yield).

Intermediate 17:[2-Bromo-4-(3-fluoro-pyridin-4-ylcarbamoyl)-benzyl]-carbamic acidtert-butyl ester

Intermediate 17 was prepared as described for Intermediate 16.

Intermediate 18:2′-(tert-Butoxycarbonylamino-methyl)-5′-(pyridin-4-ylcarbamoyl)-biphenyl-3-carboxylicacid

To a solution of Intermediate 16 (35 g, 0.086 mol, 1.0 eq) and3-carboxyphenylboronic acid (14.27 g, 0.086, 1.0 eq) in DMF (350 ml) andH₂O (87.5 ml) was added Na₂CO₃ (18.2 g, 0.172 mol, 2.0 eq). ThenPd(dppf)Cl₂ (3.15 g, 0.0043 mol, 0.05 eq) was added to the solutionunder N₂. The resulting solution was stirred at 100° C. for 16 hrs.Solvent was evaporated under vacuum and the residue was purified bycolumn chromatography on silica gel using DCM: MeOH=10:1 to give thetitle compound (27 g, 70% yield) as brown solid.

Intermediate 19:2′-(tert-Butoxycarbonylamino-methyl)-5′-(3-fluoro-pyridin-4-ylcarbamoyl)-biphenyl-3-carboxylicacid

Intermediate 19 was prepared as described for Intermediate 18 startingfrom intermediate 17.

The following intermediates were prepared in a similar way:

Name Intermediate Structure 2′-(tert- Butoxycarbonylamino-methyl)-5′-(3-fluoro- pyridin-4- ylcarbamoyl)- biphenyl-4-carboxylicacidr 20

[3′-Hydroxy-5- (pyridin-4- ylcarbamoyl)- biphenyl-2-ylmethyl]- carbamicacid tert- butyl ester 21

[5-(3-Fluoro-pyridin- 4-ylcarbamoyl)-3′- hydroxy-biphenyl-2-ylmethyl]-carbamic acid tert-butyl ester 22

[3′-Amino-5-(pyridin- 4-ylcarbamoyl)- biphenyl-2-ylmethyl]- carbamicacid tert- butyl ester 23

[3′-Amino-5-(3- fluoro-pyridin-4- ylcarbamoyl)- biphenyl-2-ylmethyl]-carbamic acid tert- butyl ester 24

(E/Z)-3-[2′-(tert- Butoxycarbonylamino- methyl)-5′-(pyridin-4-ylcarbamoyl)- biphenyl-3-yl]-acrylic acid 25

[2′-(tert- Butoxycarbonylamino- methyl)-5′-(3-fluoro- pyridin-4-ylcarbamoyl)- biphenyl-3-yl]-acetic acid 26

Intermediate 27[2′-(tert-Butoxycarbonylamino-methyl)-5′-(pyridin-4-ylcarbamoyl)-biphenyl-3-yloxy]-aceticacid

To a solution of common intermediate (30 g, 0.074 mol, 1.0 eq) and[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-acetic acidethyl ester (23 g, 0.074, 1.0 eq) in DMF (300 ml) and H₂O (75 ml) wasadded Na2CO3 (15.6 g, 0.147 mol, 2.0 eq). Then added Pd(dppf)Cl2 (2.7 g,0.0037 mol, 0.05 eq) to the solution under N2. The resulting solutionwas stirred at 100° C. for 16 hrs. Evaporated the solvent and theresidue was dissolved in MeOH 200 ml, added into 148 ml 1M LiOH, theresulting solution was stirred at 30° C. for 16 hrs, checked by LC-MS.Evaporated the solvent to 1/3 then adjusted the pH=5 with 20% aqueoushydrochloric acid, then evaporated the solvent and the residue waspurified by column chromatography on silica gel using DCM: MeOH=10:1 togive the title compound (23.8 g, 67.4% two steps) as white solid.

Intermediate 28[2′-(tert-Butoxycarbonylamino-methyl)-5′-(3-fluoro-pyridin-4-ylcarbamoyl)-biphenyl-3-yloxy]-aceticacid

Intermediate 28 was prepared as described for Intermediate 27 startingfrom intermediate 17.

When a compound of the invention contains an ester group, it can be madeas described in the general scheme below:

Protocol E.

To a suspension of the corresponding carboxylic acid (0.25 mmol) in DMF(1 mL) were added DIEA (0.75 mmol, 3 eq), TBTU (0.325 mmol, 1.3 eq),HOBt (0.075 mmol, 0.3 eq) and the reaction mixture was stirred at rt for5 min followed by addition of the corresponding alcohol (1.1-5 eq). Thereaction mixture was stirred at rt for 1-16 h, then diluted with ethylacetate (100 mL), washed with aqueous saturated sodium carbonatesolution (50 mL), 0.1M HCl (50 mL), water (50 mL) and brine (50 mL). Theorganic phase was then dried over MgSO₄ and concentrated in vacuo toafford the desired ester.

Alternative protocol.

Acids of the general type can be converted to the corresponding estersaccording to the Steglich method mediated by action of DCC in thepresence of DMAP. This chemistry is well known to those skilled in theart and can be performed according to the literature precedents (B.Neises and W. Steglich. “Esterification of carboxylic acids withdicyclohexyl carbodiimide/4-dimethylaminopyridine”; Coll. Vol. 7: 93)

Protocol F.

To a solution of the corresponding carboxylic acd (0.25 mmol) in THF orDCM (1 mL) cooled to 00° C. was added Ghosez reagent(1-chloro-N,N,2-trimethyl-1-propenylamine, CAS number 26189-59-3, 0.5mmol, 2 eq). The reaction mixture was stirred for 1-3 h while beingwarmed up to rt followed by addition of the corresponding alcohol (1.2eq). The reaction mixture was stirred at rt for 1 h. The solvent wasevaporated in vacuo. The residue was diluted with EtOAc and washed withsaturated NaHCO₃. The organic layer was dried over MgSO₄ and the solventwas removed under reduced pressure

General scheme for conversion of acids into thioesters.

To a solution of the corresponding carboxylic acid (1 mmol) in DCM orDMF at 00° C. (10 mL) were added DCC (1.1 mmol, 1.1 eq) and DMAP (0.1mmol, 0.1 eq) followed by addition of the corresponding thiol (2-4 eq).The cooling bath was removed and the reaction mixture as stirred at rtfor 1-16 h. The reaction mixture was diluted with DCM (100 mL), washedwith aqueous saturated sodium carbonate solution (50 mL), 0.1M HCl (50mL), water (50 mL) and brine (50 mL). The organic phase was then driedover MgSO₄ and concentrated in vacuo to afford the desired thioester.

Alternative protocol: A mixture of the corresponding carboxylic acid(200 mg, 1.0 eq) and ethanethiol (2.0 eq) in CH₃CN (4 ml) was added HOBT(0.4 eq) and EDCI (about 120 mg, 1.5 eq). The reaction mixture wasstirred at 30° C. for 16 hrs. LC-MS showed the reaction was complete.Then the solvent was concentrated to dryness to give crude product,which was used directly for next step without purification.

The crude product was dissolved in DCM/TFA=7:1 (4 ml). The reactionmixture was stirred at 30° C. for 16 hrs. LC-MS showed the reaction wascomplete. Then the reaction mixture was concentrated and the crudeproduct was purified by prep HPLC to give the final product.

General Scheme for Conversion of Heteroalkyl Groups to LactoneDerivatives

Alcohols or thiols of general type can be converted to the correspondingheteroalkyl linked lactones according to the general scheme (X═O or S).

To a solution of the corresponding thiol (1 mmol) in DMF (10 mL) wasadded DIEA (2 mmol, 2 eq) followed by addition of the correspondingbromolactone (1.1 mmol, 1.1 eq). The reaction mixture was stirred at rtfor 1 h then diluted with ethyl acetate (100 mL), washed 0.1M HCl (50mL), water (50 mL) and brine (50 mL). The organic phase was then driedover MgSO₄ and concentrated in vacuo to afford the desired lactone.

Intermediate 29: 3-(2-Amino-ethylsulfanyl)-dihydro-furan-2-one

3-Bromo-dihydro-furan-2-one (2.49 g, 15.1 mmol) and2-(Boc-amino)ethanethiol (2.9 g, 16.5 mmol) were dissolved in 40 mL ofCH₃CN. Then K₂CO₃(4.14 g, 30 mmol) wasn added to the solution. Let itstir at 80° C. for 16 h. The solvent was evaporated to dryness and theresidue was purified by column chromatography (PE/EtOAc=4/1) to 3.8 g ofBOC protected Intermediate 29 as colorless oil.

The previous compound (3.7 g, 14.16 mmol) was dissolved in 10 ml ofEtOAc. Then 40 mL of 4N HCl/EtOAc was added to the solution. Let it stirat 25° C. for 2 h. The white solid was filtered and washed with PE togive 2 g of Intermediate 29.

Intermediate 30: 3-(3-Amino-propylsulfanyl)-dihydro-furan-2-one

3-Amino-propan-1-ol (40 g, 0.533 mol) was dissolved in 1 L of THF. ThenBoc₂O (127.26 g, 0.586 mol) in 450 mL of THF was added dropwise to thesolution at 25° C. Let it stir at 25° C. for 12 h. 500 mL of water wasadded to the solution and it was extracted with EtOAc (200 mL*3), driedwith MgSO₄. Filtered and evaporated to dryness to give 60 g of thecorresponding BOC protected compound as colorless oil.

Boc protected 3-Amino-propan-1-ol (30 g, 0.171 mol) was dissolved in 600mL of dry THF. TEA (48 mL, 0.345 mol) was added to the solution. ThenMsCl (26.67 mL) was added slowly to the solution at 00° C. under N₂. Letit stir at 25° C. for 2 h. The mixture was washed with water and driedwith MgSO4. Filtered and evaporated to dryness to give 40 g ofMs-protected product.

The above compound (40 g, 0.158 mol) and CH₃COSK (54.1 g, 0.474 mol )were mixed in 2.7 L of EtOH. Let it stir at 90° C. under N₂ for 16 h.The solvent was evaporated to dryness and the mixture was purified bycolumn chromatography (PE/EA=10/1) to give 15 g of thioacetic acidS-(3-tert-butoxycar bonylamino-propyl) ester as orange solid.

Na (708 mg, 30.8 mmol) was added into 100 mL of dry methanol and stirreduntil the metal sodium disappeared. To the solution was added the abovecompound (6 g, 25.8 mmol). The mixture was stirred at room temperaturefor 2 hours. TLC showed the reaction was completed. To the mixture wasadded a solution of 3-Bromo-dihydro-furan-2-one (5.46 g, 33.3 mmol) in100 mL of CH₂Cl₂ followed by addition of 100 mL of DMF. The resultingmixture was stirred at 60° C. for 6 hours. TLC showed the reaction wascompleted. The reaction mixture was partitioned between 800 mL of EA and400 mL of water and the aqueous layer was extracted by EA (800 mL×2).The combined organic layers were dried, filtered and concentrated togive the crude product, which was purified by column chromatography(PE/EA=4/1) to give 3.5 g of the title BOC protected compound ascolorless oil.

The BOC protected derivative (3.5 g, 12.71 mmol) was dissolved in 10 mlof EtOAc. Then 40 mL of 4N HCl/EtOAc was added to the solution. Thereaction mixture was stirred at 25° C. for 2 h. The white solid wasfiltered and washed with PE to give 2.5 g of the title compound.

Intermediate 30: 4-(2-Amino-ethyl)-[1,3]dioxolan-2-one

60 mL saturated solution of NH₃ in CH₃OH was added to 4-bromo-but-1-ene(3 mL) quickly in a 100 mL reactor of autoclave. Then the mixture wasstirred at 90° C. for 16 hours in the autoclave. After reaction, theremained solvent was removed under vacuo. The hydrobromide salt ofbut-3-enylamine (12 g, 95%) was recovered as a yellow power.

To a suspension of the previous compound (12 g, 0.08 mol) in CH₂Cl₂ (1L) was added a solution of K₂CO₃ (33 g, 0.24 mol) in water (80 mL) underN₂. The bi-phasic mixture was cooled to 0° C. and Cbz-Cl (22 g, 0.128mol) was added dropwise. After 15 min of stirring at the temperature,the reaction mixture was stirred for 14 hours at room temperature. Afterthe reaction completed, to the mixture was added CH₂Cl₂ and water, theorganic layer was dried over anhydrous Na₂SO₄, concentrated under vacuumand purified through silica gel chromatography (petroleum/ethylacetate=3:1) to give the corresponding Cbz protected compound (12.2 g,75%) as colorless oil.

To a stirred solution of the above compound (12.2 g, 59.5 mmol) inacetone/H₂O (60 mL/50 mL) was added NMO (7.3 g, 62.5 mmol) and OsO₄ (303mg, 1.2 mmol) at room temperature under N₂. After addition of OsO₄, thecolor of reaction solution turned black. Then the mixture was stirred atroom temperature for 10 h. TLC (CH₂Cl₂/MeOH=10:1) showed the startingmaterial was consumed completely. The mixture was evaporated undervacuo. To the residue was added water and extracted with ethyl acetate.The organic layer was dried over anhydrous Na₂SO₄, concentrated undervacuum and purified through silica gel chromatography (CH₂Cl₂/MeOH=10:1)to give the corresponding diol (12 g, 85%) as pale solid.

To a solution of the diol (9 g, 37.66 mmol) in CH₂Cl₂ (200 mL) was addedtriethylamine (15.2 g, 151 mmol) at −20-30° C. under N₂. After severalminutes, triphosgene (5.5 g, 18.83 mmol) was added to the mixturedropwise at this temperature and stirred at −20˜30° C. for half an hour.Then the mixture was stirred at room temperature for 15 h. TLC(CH₂Cl₂/MeOH=10:1) showed the starting material was almost consumed. Tothe mixture was added water and extracted with ethyl acetate. Theorganic layer was dried over anhydrous Na₂SO₄, concentrated under vacuumand purified through silica gel chromatography (CH₂Cl₂/MeOH=10:1) togive the corresponding cyclized dioxolane (6.5 g, 55%) as pale solid.

To a solution of the above compound (5.5 g, 20.5 mmol) in CH₃OH (100 mL)was added dry Pd/C (550 mg, 10%) quickly under N₂. Then the mixture wasstirred at room temperature under H₂ overnight. TLC (CH₂Cl₂/MeOH=10:1)showed the starting material was almost consumed. The mixture wasfiltered via a pad of celite. The solution was evaporated under vacuoand purified by silica gel (CH₂Cl₂/MeOH=10:1) to give the titleintermediate (2.0 g, 77%) as white solid.

Intermediate 31: 3-(2-Hydroxy-ethylsulfanyl)-dihydro-furan-2-one

To a solution of 2-mercapto-ethanol (2560 μmol) in THF (4 ml) were addedDIEA (1.1 eq) and 3-bromo-dihydro-furan-2-one (1 eq). The reactionmixture was stirred at RT for 4 hours. The precipitate was filtered andthe solvent was removed under reduced pressure.

Intermediate 32: 3-(3-Hydroxy-propylsulfanyl)-dihydro-furan-2-one

To a solution of 3-mercapto-propan-1-ol (1685 μmol) in DMF (2 ml) wereadded DIEA (1.5 eq) and 3-bromo-dihydro-furan-2-one (1 eq). The reactionmixture was stirred at RT for 4 hours. The precipitate was filtered andthe solvent was removed under reduced pressure.

Intermediate 33: 3-bromomethyl-oxetan-2-one

To a solution of Br₂ (4.86 g, 0.0303 mol) in ether (150 mL) was addeddropwise a solution of compound but-3-enoic acid (2.6 g, 0.0302 mol) insaturated NaHCO₃ (110 mL) at 00° C. After addition the mixture wasstirred for 1 h. TLC (PE:EA=4:1) showed the reaction was complete.Saturated solution (20 mL) was added. The reaction was extracted withEtOAc (100 mL×3). The combined layers were washed with brine, dried overNa₂SO₄, filtered and then concentrated in vacuo and purified by columnchromatography on silica gel (petroleum ether/ethyl acetate=20:1) toobtain the title compound (1.73 g, 35%) as a white oil.

Intermediate 34: 3-(Piperidin-4-ylmethylsulfanyl)-dihydro-furan-2-one

Intermediate 34 was prepared as described for Intermediate 30 startingfrom 4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester.

Intermediate 35: 3-(2-hydroxy-ethoxy)-dihydro-furan-2-one

A solution of 50 g of 2,3-dihydro-furan in methanol 700 mL andchloroform 300 mL was added 90 g of m-chloroperoxybenzoic acid in smallportions with stirring at 000° C. for 15 mins, then the reaction mixturewas stirred at 25° C. for 15 hrs. The resulting mixture was filtered,the filtrate was concentrated under reduced pressure, the residue wasdissolved in chloroform 500 ml, washed with 200 mL of sat. NaHCO₃ and200 mL of brine, The organic layer was dried over Na₂SO4 and filtered.The filtrate was concentrated under reduced pressure to afford 30 g of2-methoxy-tetrahydro-furan-3-ol.

A solution of 2-methoxy-tetrahydro-furan-3-ol in DMF 200 mL was addedsodium hydride in small portions with stirring at 0° C. for 2 hrs, then2-Benzyloxy-ethanol was added from the dropping funnel over a period of1 hour, the resulting mixture was stirred at 25° C. for 15 hrs, it waspoured into 400 mL water, EtOAC (1 L) were added and separated. Theorganic layer was washed with sat. NaHCO₃(500 mL), dried over Na2SO4,filtered and concentrated, The residue was purified by columnchromatography (PE:EA=5:1) to yield 10 g of3-(2-Benzyloxy-ethoxy)-2-methoxy-tetrahydro-furan (oil).

To a solution of the previous compound in 300 mL of 40% aqueous MeCN wasadded 30 mL of concentrated H₂SO4 and the mixture stirred at 35° C. for4 hrs. The resulting mixture was neutralized with NaHCO₃, then it wasconcentrated under reduced pressure, EtOAC (300 mL) were added andseparated. The organic layer was washed with brine (100 mL), dried overMgSO4, filtered and concentrated, the residue was purified by columnchromatography (PE:EA=1:1) to yield 4.8 g of3-(2-benzyloxy-ethoxy)-tetrahydro-furan-2-ol (oil).

To a solution of the above compound in 25 mL of DMSO was added 17 mL ofAc₂O with stirring at 25° C. for 15 hrs, the resulting mixture waspoured into 100 mL of water, EtOAc (200 mL) were added and separated.The organic layer was washed with sat. NaHCO₃ (50 mL) and brine (50 mL),dried over MgSO4, filtered and concentrated. The residue was purified bycolumn chromatography (PE:EA=5:1) to yield 2.5 g of3-(2-benzyloxy-ethoxy)-dihydro-furan-2-one (oil).

A mixture of the above compound and 0.5 g of palladium on charcoal in100 mL of methanol was stirred under 1 atm of H₂ 25° C. for 5 hrs, theresulting mixture was filtered and filtrate was concentrated underreduced pressure to afford 1.35 g of Intermediate 35 (oil).

Intermediate 36: 3-hydroxymethyl-dihydro-thiophen-2-one

Thiobutyrolactone (10 g, 97.9 mmol) in anhydrous tetrahydrofuran (200ml) was added dropwise to a stirred solution of lithium diisopropylamide[Diisopropylamine (15.1 g, 117.5 mmol) and n-butyllithium in hexane 2.5M(47.0 ml, 117.5 mmol) at −78° C.]. The resulting solution was stirredfor 10 minutes at which time formaldehyde (50 g) carried in a stream ofN₂ was added [Formaldehyde was formed by heating paraformaldehyde to150° C.]. The reaction was allowed to proceed for 2.5 h at −78° C. Theformaldehyde stream was removed and reaction was allowed to proceed foran additional 30 mins. Then 300 ml of ethyl acetate was poured into thereaction mixture while stirring then quenched by the addition of (300ml) 1M HCl at −78° C. then allowed to warm to room temperature whilefiltering through a bed of celite. The filtrate was extracted with ethylacetate 100 ml for more than 5 times and the combined organic layerswere dried (Na₂SO₄) and concentrated to an oil. The oil was purified bychromatography (PE/EA=9/1) to give 1.70 g of the title compound ascolorless oil.

Intermediate 37: 3-hydroxymethyl-dihydro-furan-2-one

To a stirred suspension of NaH (9.77 g, 244 mmol, 60%) in 250 ml of THFwas added dropwise the mixture of 20 g of γ-butyrolactone (20 g, 232mmol) and methyl formate (14 g, 232 mmol). The resulting mixture wasstirred at 25° C. for 20 hrs. The solid material was filtered and washedwith hexane, after which it was suspended dry methanol (800 ml). Asolution of HCl-MeOH (4M) was added dropwise and the mixture was stirredfor 1 hr. After carefully neutralization with NaOH, the mixture wasfiltered and the filtrate was carefully concentrated. Water was addedand the solution was worked up as usual to afford 23 g of crude ester.Vacuum distillation (100-120° C., 20 mmHg) afforded 14 g of2-methoxy-tetrahydro-furan-3-carboxylic acid methyl ester as a colorlessoil.

To a solution of 2-methoxy-tetrahydro-furan-3-carboxylic acid methylester (10 g, 62.5 mmol) in 60 ml of dry THF was added 4.75 g (125 mmol)LiAlH₄ at 25° C. The mixture was refluxed for 4 hrs and cooled. 4.75 mlof H₂O and 4.75 ml of aq. NaOH (10%) were added to the reaction mixturein turn. The resulting mixture was filtered and the filtrate wasconcentrated to yield (2-methoxy-tetrahydro-furan-3-yl)-methanol (7 g).

To a solution of the above compound (7 g, 53 mmol) in 300 ml of DMF wasadded NaH (3.2 g, 80 mmol, 60%), followed by BnBr (12.4 ml, 106 mmol).The resulting mixture was stirred at 25° C. for 2 hrs and then pouredinto 1 L of water. And then the mixture was extracted with EtOAc (500ml*3). The combined organic layer was dried over MgSO₄, filtered, andconcentrated. The residue was purified by column chromatography(PE:EA=2:1) to afford 3-benzyloxymethyl-2-methoxy-tetrahydro-furan (10g).

To a solution of the previous compound (10 g, 45 mmol) in DCM (180 ml)was added BF₃.Et₂O (3.4 ml) and m-CPBA (9.86 g, 48.75 mmol, 85%). Theresulting mixture was stirred at 25° C. overnight. The reaction mixturewas diluted with EtOAc (500 ml) and washed with 10% Na₂S2O₃, sat. NaHCO₃and brine. The organic layer was dried over MgSO4, filtered andconcentrated. The residue was purified by column chromatography toafford the benzyl-protected intermediate 37 (6.7 g).

To a solution of the above compound (6.7 g, 32.5 mmol) in EtOH (200 ml)was added 1 g of 10% of Pd/C and hydrogenated for 10 hrs at 25° C., 1atm. The mixture was filtered and concentrated to afford the titlecompound (3.9 g).

Intermediate 38: 5-(2-hydroxy-ethyl)-3H-furan-2-one

To a cooled solution of furan (3.40 g, 50.0 mmol) in THF (150 mL) wasadded n-BuLi (22 mL, 2.5M solution in hexane, 55.0 mmol) at 00° C. underinert gas atmosphere. The solution was allowed to warm to roomtemperature and stirred for 3 h. Then TMSCl (5.34 g, 50 mmol) was addeddropwise at 0° C. and the solution was stirred for further 3 h at roomtemperature. Subsequently, the solution was again cooled to 00° C. andn-BuLi (22 mL, 2.5M solution in hexane, 55.0 mmol) was added a secondtime. After stirring for 3 h at room temperature ethyleneoxide (2.42 g,55.0 mmol) was condensed by an acetone/dry ice condenser into thesolution and the solution was stirred for further 12 h at roomtemperature. The mixture was quenched with aq NH₄Cl, and then extractedwith EtOAc and the combined organic layers were dried over Na₂SO₄ toafforded the desired product (5 g, 27.1 mmol, 54% over two steps) as ayellow liquid.

To a solution of the above compound (3 g, 16.45 mmol) and NaOAc (1.64 g,20 mmol) in CH₂Cl₂ (30 mL) was added dropwise a solution of CH₃CO₃H (16g, 40% in H₂O) in CH₂Cl₂ (90 mL). The reaction mixture was stirred forovernight at room temperature. The reaction was quenched with Na₂SO₃,washed with saturated NaHCO₃ and brine. The organic layer wasconcentrated under reduced pressure. The resulting residue was purifiedby column chromatography (PE:EA=1:2) to give 0.5 g of desired product asa yellow liquid (0.5 g, yield: 24%).

Intermediate 39: (2-Oxo-tetrahydro-furan-3-ylsulfanyl)-acetic acid

Potassium ethylxanthate (58.0 g, 364 mmol) was suspended in 200 mL ofdry acetone at room temperature. tert-Butyl chloroacetate (50 g, 332mmol) was added dropwise with stirring. After 18 hrs potassium chloridewas removed by filtration, and the solvent was evaporated. The residuewas taken up into ether, washed with 5% NaHCO₃, water, and brine, driedover MgSO₄, filtered, and evaporated to leave 80 g of O-ethylS-(tert-butoxycarbonyl)methyl dithiocarbonate as a thick oil. This oilwas stirred with ethanolamine (323 mmol) for 2 hrs at room temperature.The reaction mixture was taken up into ethyl acetate, washed with 1.2NHCl, water, and brine, dried over MgSO₄, filtered, and evaporated. Theresidue was vacuum dis-tilled to give 30 g of mercapto-acetic acidtert-butyl ester as a clear oil.

To a solution of 3-bromo-dihydro-furan-2-one (16 g, 97.6 mmol) in 300 mLof CH₃CN was added K₂CO₃ (20 g, 146 mmol), followed by mercapto-aceticacid tert-butyl ester (14.5 g, 98 mmol). The reaction mixture wasrefluxed for 2 hrs and cooled. The mixture was filtered and the filtratewas concentrated. The residue was redissolved in 300 mL of EtOAc and theresulting solution was washed with 1N HCl (100 mL*2). The organic layerwas dried over MgSO₄, filtered and concentrated to afford the ter-butylester title compound (23 g). 16 g of the ester was dissolved in 250 mlof HCl-MeOH (4M) and stirred at 25° C. for 4 hrs. The reaction mixturewas concentrated below 45° C. in vacuum. The residue was purified bycolumn chromatography (EtOAc) to afford 7 g of the title compound.

B.1. Compounds of the Invention

In the tables 1 to 19 that are set forth below, exemplary compounds ofthe invention are set out in tabulated form. In these tables, the nameof the compound, an arbitrarily assigned compound number and structuralinformation are set out.

Table 1 shows the results for compounds of Formula IIa or IIb

TABLE 1 Name Cpd Ar —R¹ Formula —R²¹ 2′-Aminomethyl- 5′-(pyridin-4-ylcarbamoyl)- biphenyl-3- carboxylic acid methyl ester 1

—H IIa

2′-Aminomethyl- 5′-(pyridin-4- ylcarbamoyl)- biphenyl-4- carboxylic acidmethyl ester 2

—H IIb

2′-Aminomethyl- 5′-(pyrimidin-4- ylcarbamoyl)- biphenyl-3- carboxylicacid methyl ester 3

—H IIa

2′-(1-Amino- ethyl)-5′- (pyridin-4- ylcarbamoyl)- biphenyl-3- carboxylicacid methyl ester 4

—Me IIa

2′-(1-Amino- ethyl)-5′-(3-fluoro- pyridin- 4-ylcarbamoyl)- biphenyl-3-carboxylic acid methyl ester 5

—Me IIa

2′-(1-Amino-ethyl)- 5′-(1H- pyrrolo[2,3-b]pyridin- 4-ylcarbamoyl)-biphenyl-3-carboxylic acid methyl ester 6

—Me IIa

2′-Aminomethyl- 5′-(pyridin-4- ylcarbamoyl)- biphenyl-3- carboxylic acidethyl ester 7

—H IIa

2′-(1-Amino-ethyl)- 5′-(pyridin-4- ylcarbamoyl)- biphenyl-3- carboxylicacid ethyl ester 8

—Me IIa

2′-(1-Amino-ethyl)- 5′-(3-fluoro- pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylic acid ethyl ester 9

—Me IIa

2′-Aminomethyl-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3- carboxylic acidpropyl ester 10

—H IIa

2′-(1-Amino-ethyl)- 5′-(pyridin-4- ylcarbamoyl)- biphenyl-3-carboxylicacid propyl ester 11

—Me IIa

2′-(1-Amino-ethyl)-5′- (3-fluoro-pyridin-4- ylcarbamoyl)-biphenyl-3-carboxylic acid propyl ester 12

—Me IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid butyl ester 13

—Me IIa

2′-Aminomethyl-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylic acidbutyl ester 14

—H IIa

2′-Aminomethyl-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylic acidpentyl ester 15

—H IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid pentyl ester 16

—Me IIa

2′-Aminomethyl-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylic acidhexyl ester 17

—H IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid heptyl ester 18

—Me IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid octyl ester 19

—Me IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid decyl ester 20

—Me IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid undecyl ester 21

—Me IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid dodecyl ester 22

—Me IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid tridecyl ester 23

—Me IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid hexadecyl ester 24

—Me IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid dec-9-enyl ester 25

—Me IIa

2′-Aminomethyl-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylic acidisopropyl ester 26

—H IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid isopropyl ester 27

—Me IIa

2′-(1-Amino-ethyl)-5′- (3-fluoro-pyridin-4- ylcarbamoyl)-biphenyl-3-carboxylic acid isobutyl ester 28

—Me IIa

2′-Aminomethyl-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylic acidtert-butyl ester 29

—H IIa

2′-Aminomethyl-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylic acidcyclopropyl ester 30

—H IIa

2′-Aminomethyl-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylic acidcyclobutyl ester 31

—H IIa

2′-Aminomethyl-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylic acidcyclopentyl ester 32

—H IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid cyclopentyl ester 33

—Me IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid cyclohexyl ester 34

—Me IIa

2′-Aminomethyl-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylic acidcyclohexyl ester 35

—H IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid cyclopropylmethyl ester 36

—Me IIa

2′-(1-Amino-ethyl)-5′- (3-fluoro-pyridin-4- ylcarbamoyl)-biphenyl-3-carboxylic acid cyclopropylmethyl ester 37

—Me IIa

2′-Aminomethyl-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylic acidcyclopentylmethyl ester 38

—H IIa

2′-Aminomethyl-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylic acidcyclohexylmethyl ester 39

—H IIa

2′-(1-Amino-ethyl)- 5′-(pyridin-4- ylcarbamoyl)-biphenyl- 3-carboxylicacid isobutyl ester 40

—Me IIa

2′-Aminomethyl-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylic acid2-methoxy-ethyl ester 41

—H IIa

2′-Aminomethyl-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylic acid2-methoxy-propyl ester 42

—H IIa

2′-Aminomethyl-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylic acidtetrahydro-pyran-4-yl ester 43

—H IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid tetrahydro-furan-2- ylmethyl ester 44

—Me IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid tetrahydro-pyran-2- ylmethyl ester 45

—Me IIa

2′-(1-Amino-ethyl)-5′- (3-fluoro-pyridin-4- ylcarbamoyl)-biphenyl-3-carboxylic acid tetrahydro-furan- 2-ylmethyl ester 46

—Me IIa

2′-(1-Amino-ethyl)-5′- (3-fluoro-pyridin-4- ylcarbamoyl)-biphenyl-3-carboxylic acid tetrahydro-pyran-2- ylmethyl ester 47

—Me IIa

2′-Aminomethyl-5′- (pyridin-4- ylcarbamoyl)-biphenyl- 3-carboxylic acid1-methyl-piperidin- 4-yl ester 48

—H IIa

2′-Aminomethyl-5′- (pyridin-4- ylcarbamoyl)-biphenyl- 3-carboxylic acid2-oxo-[1,3]dioxolan- 4-yl ester 49

—H IIa

2′-Aminomethyl-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylic acid5-methyl-2-oxo-[1,3]dioxol- 4-ylmethyl ester 50

—H IIa

2′-Aminomethyl-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylic acidadamantan-1-ylmethyl ester 51

—H IIa

2′-Aminomethyl-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylic acidchloromethyl ester 52

—H IIa

2′-Aminomethyl-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylic acid2-fluoro-phenyl ester 53

—H IIa

2′-Aminomethyl-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylic acidthiophen-2-ylmethyl ester 54

—H IIa

2′-Aminomethyl-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylic acid2,3-dihydro- benzo[1,4]dioxin-2-ylmethyl ester 55

—H IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid 2,3-dihydro- benzo[1,4]dioxin-2-ylmethyl ester 56

—Me IIa

2′-Aminomethyl-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylic acidbutyryloxymethyl ester 57

—H IIa

2′-(2-Amino-ethyl)-5′- (pyidin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid prop-2-ynyl ester 58

—Me IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid but-2-ynyl ester 59

—Me IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid 2-fluoro-ethyl ester 60

—Me IIa

2′-(1-Amino-ethyl)-5′-(3- fluoro-pyridin-4- ylcarbamoyl)-biphenyl-3-carboxylic acid 2-fluoro- ethyl ester 61

—Me IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid 2-chloro-ethyl ester 62

—Me IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid 2,2,2-trifluoro-ethyl ester 63

—Me IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid 2,2,2-trichloro-ethyl ester 64

—Me IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid 2-hydroxy-ethyl ester 65

—Me IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid 3-hydroxy-propyl ester 66

—Me IIa

2′-(1-Amino-ethyl)-5′-(3- fluoro-pyridin-4-ylcarbamoyl)-biphenyl-3-carboxylic acid 2-hydroxy-ethyl ester 67

—Me IIa

2′-(1-Amino-ethyl)-5′-(3- fluoro-pyridin-4-ylcarbamoyl)-biphenyl-3-carboxylic acid 3-hydroxy-propyl ester 68

—Me IIa

2′-(1-Amino-ethyl)-5′-(pyridin- 4-ylcarbamoyl)-biphenyl- 3-carboxylicacid 4-chloro- butyl ester 69

—Me IIa

2′-(1-Amino-ethyl)-5′-(pyridin- 4-ylcarbamoyl)-biphenyl- 3-carboxylicacid phenyl ester 70

—Me IIa

2′-(1-Amino-ethyl)-5′- (3-fluoro-pyridin-4- ylcarbamoyl)-biphenyl-3-carboxylic acid phenyl ester 71

—Me IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid 4-fluoro-phenyl ester 72

—Me IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid p-tolyl ester 73

—Me IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid 2,6-dimethoxy-phenyl ester 74

—Me IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid 3,5-dimethoxy-phenyl ester 75

—Me IIa

2′-(1-Amino-ethyl)-5′- (3-fluoro-pyridin-4- ylcarbamoyl)-biphenyl-3-carboxylic acid 3,5- dimethoxy-phenyl ester 76

—Me IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid 3,4-dimethoxy-phenyl ester 77

—Me IIa

2′-(1-Amino-ethyl)-5′- (3-fluoro-pyridin-4- ylcarbamoyl)-biphenyl-3-carboxylic acid 3,4- dimethoxy-phenyl ester 78

—Me IIa

2′-(1-Amino-ethyl)-5′- (3-fluoro-pyridin-4- ylcarbamoyl)-biphenyl-3-carboxylic acid 3,4,5- trimethoxy phenylester 79

—Me IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid 3,4,5-trimethoxy-phenyl ester 80

—Me IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid 2,3,4-trimethoxy-phenyl ester 81

—Me IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid 4-methylsulfanyl-phenyl ester 82

—Me IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid pentafluoro-phenylmethyl ester 83

—Me IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid 4-bromo-benzyl ester 84

—Me IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid 2-nitro-benzyl ester 85

—Me IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid 4-methylsulfanyl-phenyl ester 86

—Me IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid phenethyl ester 87

—Me IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid 3-phenoxy-propyl ester 88

—Me IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid 2-(toluene-4-sulfonyl)-ethyl ester 89

—Me IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid furan-3-ylmethyl ester 90

—Me IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid 2-thiophen-2-yl-ethyl ester 91

—Me IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid 2-thiophen-3-yl-ethyl ester 92

—Me IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid 2-pyridin-2-yl-ethyl ester 93

—Me IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid 1,2,3,4-tetrahydro-naphthalen- 2-ylmethyl ester 94

—Me IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid 2-(1,3-dioxo-1,3-dihydro- isoindol-2-yl)-ethyl ester 95

—Me IIa

2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)- biphenyl-3-carboxylicacid 2-(4-bromo-phenyl)-2-oxo- ethyl ester 96

—Me IIa

Table 2 shows the results for compounds of Formula IIIa or IIIb

TABLE 2 Name Cpd Ar —R¹ Formula —R²² 2′- Aminomethyl- 5′-(pyridin-4-ylcarbamoyl)- biphenyl-3- carbothioic acid S-ethyl ester  97

—H IIIa

2′- Aminomethyl- 5′-(pyridin-4- ylcarbamoyl)- biphenyl-4- carbothioicacid S-ethyl ester  98

—H IIIb

2′- Aminomethyl- 5′-(pyridin-4- ylcarbamoyl)- biphenyl-3- carbothioicacid S-fluoromethyl ester  99

—H IIIa

2′- Aminomethyl- 5′-(pyridin-4- ylcarbamoyl)- biphenyl-4- carbothioicacid S-fluoromethyl ester 100

—H IIIb

2′-(1-Amino- ethyl)-5′- (pyridin-4- ylcarbamoyl)- biphenyl-3-carbothioic acid S-tert-butyl ester 101

—Me IIIa

Table 3 shows the results for compounds of Formula IVa and IVb.

TABLE 3 Name Cpd Ar Formula —R¹ —R³ —R⁴ {[2′-Aminomethyl-5′-(pyridin-4-ylcarbamoyl)-biphenyl-3- carbonyl]-amino}-acetic acid methyl ester 102

IVa —H —H

{[2′-Aminomethyl-5′-(pyridin-4- ylcarbamoyl)-biphenyl-4-carbonyl]-amino}-acetic acid methyl ester 103

IVb —H —H

{[2′-Aminomethyl-5′-(pyridin-4- ylcarbamoyl)-biphenyl-3-carbonyl]-amino}-acetic acid ethyl ester 104

IVa —H —H

3-{[2′-(1-Amino-ethyl)-5′- (pyridin-4-ylcarbamoyl)-biphenyl-3-carbonyl]-amino}- propionic acid ethyl ester 105

IVa —Me —H

6-Aminomethyl-biphenyl-3,3′- dicarboxylic acid 3′- carbamoylmethyl-amide3- pyridin-4-ylamide 106

IVa —H —H

2-{[2′-Aminomethyl-5′-(pyridin- 4-ylcarbamoyl)-biphenyl-3-carbonyl]-amino}-3-methyl- pentanoic acid methyl ester 107

IVa —H —H

2-(2-{[2′-Aminomethyl-5′- (pyridin-4-ylcarbamoyl)-biphenyl-3-carbonyl]-amino}- acetylamino)-propionic acid methyl ester108

IVa —H —H

6-Aminomethyl-biphenyl-3,3′- dicarboxylic acid 3′-{[(carbamoylmethyl-carbamoyl)- methyl]-amide} 3-pyridin-4- ylamide 109

IVa —H —H

{[2′-Aminomethyl-5′-(pyridin-4- ylcarbamoyl)-biphenyl-3-carbonyl]-amino}-thioacetic acid S-ethyl ester 110

IVa —H —H

{[2′-Aminomethyl-5′-(pyridin-4- ylcarbamoyl)-biphenyl-3-carbonyl]-amino}-thioacetic acid S-fluoromethyl ester 111

IVa —H —H

6-(1-Amino-ethyl)-biphenyl-3,3′- dicarboxylic acid 3′-[(2-oxo-tetrahydro-thiophen-3-yl)-amide] 3-pyridin-4-ylamide 112

IVa —Me —H

6-Aminomethyl-biphenyl-3,3′- dicarboxylic acid 3′-{[2-(2-oxo-[1,3]dioxolan-4-yl)-ethyl]- amide} 3-pyridin-4-ylamide 113

IVa —H —H

6-Aminomethyl-biphenyl-3,3′- dicarboxylic acid 3′-{[2-(5-methyl-2-oxo-[1,3]dioxol-4-yl)- ethyl]-amide} 3-pyridin-4- ylamide 114

IVa —H —H

6-Aminomethyl-biphenyl-3,3′- dicarboxylic acid 3′-{[2-(4-oxo-oxetan-2-yl)-ethyl]-amide} 3- pyridin-4-ylamide 115

IVa —H —H

6-Aminomethyl-biphenyl-3,3′- dicarboxylic acid 3′-{[2-(2-oxo-tetrahydro-pyran-4-yl)-ethyl]- amide} 3-pyridin-4-ylamide 116

IVa —H —H

6-Aminomethyl-biphenyl-3,3′- dicarboxylic acid 3′-{[2-(6-oxo-tetrahydro-pyran-2-yl)-ethyl]- amide} 3-pyridin-4-ylamide 117

IVa —H —H

6-Aminomethyl-biphenyl-3,3′- dicarboxylic acid 3′-{[2-(2-oxo-tetrahydro-pyran-3-yl)-ethyl]- amide} 3-pyridin-4-ylamide 118

IVa —H —H

6-Aminomethyl-biphenyl-3,3′- dicarboxylic acid 3′-{[2-(5-oxo-4,5-dihydro-furan-2-yl)-ethyl]- amide} 3-pyridin-4-ylamide 119

IVa —H —H

6-Aminomethyl-3′-[4-(2-oxo- tetrahydro-furan-3-ylsulfanylmethyl)-piperidine-1- carbonyl]-biphenyl-3-carboxylic acidpyridin-4-ylamide 120

IVa —H

6-Aminomethyl-3′-[4-(2-oxo- tetrahydro-furan-3-yloxymethyl)-piperidine-1-carbonyl]-biphenyl- 3-carboxylic acid pyridin-4- ylamide121

IVa —H

1-[2′-Aminomethyl-5′-(pyridin-4- ylcarbamoyl)-biphenyl-3-carbonyl]-piperidine-2- carboxylic acid methyl ester 122

IVa —H

1-[2′-Aminomethyl-5′-(pyridin-4- ylcarbamoyl)-biphenyl-3-carbonyl]-piperidine-3- carboxylic acid methyl ester 123

IVa —H

1-[2′-Aminomethyl-5′-(pyridin-4- ylcarbamoyl)-biphenyl-3-carbonyl]-piperidine-4- carboxylic acid methyl ester 124

IVa —H

1-[2′-Aminomethyl-5′-(pyridin-4- ylcarbamoyl)-biphenyl-3-carbonyl]-pyrrolidine-2- carboxylic acid methyl ester 125

IVa —H

({1-[2′-Aminomethyl-5′-(pyridin- 4-ylcarbamoyl)-biphenyl-3-carbonyl]-pyrrolidine-2- carbonyl}-amino)-acetic acid methyl ester 126

IVa —H

1-[2′-Aminomethyl-5′-(pyridin-4- ylcarbamoyl)-biphenyl-3-carbonyl]-pyrrolidine-3- carboxylic acid methyl ester 127

IVa —H

Table 4 shows the results for compounds of Formula Va and Vb.

TABLE 4 Name Cpd Ar —R¹ Formula —R¹¹ 6-Aminomethyl-3′-[2-(2-oxo-tetrahydro-furan- 3-yloxy)-ethoxy]- biphenyl-3-carboxylic acidpyridin-4-ylamide 128

—H Va

6-Aminomethyl-3′-[2- (2-oxo-tetrahydro-furan- 3-ylsulfanyl)-ethoxy]-biphenyl-3-carboxylic acid pyridin-4-ylamide 129

—H Va

6-(1-Amino-ethyl)-3′-[2- (2-oxo-tetrahydro-furan- 3-ylsulfanyl)-ethoxy]-biphenyl-3-carboxylylic acid pyridin-4-ylamide 130

—Me Va

6-(1-Amino-ethyl)-3′-[3- (2-oxo-tetrahydro-furan-3-ylsulfanyl)-propoxy]- biphenyl-3-carboxylylic acid pyridin-4-ylamide131

—Me Va

6-Aminomethyl-3′-(5- methyl-2-oxo- [1,3]dioxol-4- ylmethoxy)-biphenyl-3-carboxylic acid pyridin- 4-ylamide 132

—H Va

6-Aminomethyl-3′-(2- oxo-tetrahydro- thiophen-3-ylmethoxy)-biphenyl-3-carboxylic acid pyridin-4-ylamide 133

—H Va

6-(1-Amino-ethyl)-3′-(2- oxo-tetrahydro-furan-3- yloxy)-biphenyl-3-carboxylic acid pyridin- 4-ylamide 134

—Me Va

Table 5 shows the results for compounds of Formula VIa and VIb.

TABLE 5 Name Cpd Ar —R¹ Formula —R⁵ 6-Aminomethyl-3′-[2-(2-oxo-tetrahydro-furan-3- yloxy)-ethylamino]- biphenyl-3-carboxylic acidpyridin-4-ylamide 135

—H VIa

6-Aminomethyl-3′-[2-(2- oxo-tetrahydro-furan-3- ylsulfanyl)-ethylamino]-biphenyl-3-carboxylic acid pyridin-4-ylamide 136

—H VIa

Table 6 shows the results for compounds of Formula VIIa and VIIb.

TABLE 6 Name Cpd Ar —R¹ Formula —R²¹ [2′-Aminomethyl-5′-(pyridin-4-ylcarbamoyl)-biphenyl-3-yloxy]- acetic acid methyl ester 137

—H VIIa —Me [2′-Aminomethyl-5′-(pyridin-4-ylcarbamoyl)-biphenyl-4-yloxy]- acetic acid methyl ester 138

—H VIIb —Me [2′-Aminomethyl-5′-(pyridin-4-ylcarbamoyl)-biphenyl-3-yloxy]- acetic acid 2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester 139

—H VIIa

[2′-Aminomethyl-5′-(pyridin-4- ylcarbamoyl)-biphenyl-3-yloxy]- aceticacid propoxycarbonylmethyl ester 140

—H VIIa

[2′-(1-Amino-ethyl)-5′-(3-fluoro- pyridin-4-ylcarbamoyl)-biphenyl-3-yloxy]-acetic acid propyl ester 141

—Me VIIa

[2′-(1-Amino-ethyl)-5′-(3-fluoro- pyridin-4-ylcarbamoyl)-biphenyl-3-yloxy]-acetic acid phenyl ester 142

—Me VIIa

Table 7 shows the results for compounds of Formula VIIIa and VIIIb.

TABLE 7 Name Cpd Ar —R¹ Formula —R²² [2′-Aminomethyl-5′-(pyridin-4-ylcarbamoyl)-biphenyl-3-yloxy]- thioacetic acid S-ethyl ester 143

—H VIIIa

[2′-Aminomethyl-5′-(pyridin-4- ylcarbamoyl)-biphenyl-3-yloxy]-thioacetic acid S-fluoromethyl ester 144

—H VIIIa

[2′-Aminomethyl-5′-(pyridin-4- ylcarbamoyl)-biphenyl-4-yloxy]-thioacetic acid S-ethyl ester 145

—H VIIIb

[2′-Aminomethyl-5′-(pyridin-4- ylcarbamoyl)-biphenyl-4-yloxy]-thioacetic acid S-fluoromethyl ester 146

—H VIIIb

Table 8 shows the results for compounds of Formula IXa and IXb.

TABLE 8 Name Cpd Ar Formula —R¹ —R³ —R⁴{2-[2′-Aminomethyl-5′-(pyridin-4- ylcarbamoyl)-biphenyl-3-yloxy]-acetylamino}-acetic acid methyl ester 147

IXa —H —H

{2-[2′-Aminomethyl-5′-(3-fluoro- pyridin-4-ylcarbamoyl)-biphenyl-3-yloxy]-acetylamino}-acetic acid methyl ester 148

IXa —H —H

{2-[2′-Aminomethyl-5′-(1H- pyrrolo[2,3-b]pyridin-4-ylcarbamoyl)-biphenyl-3-yloxy]- acetylamino}-acetic acid methyl ester149

IXa —H —H

3-{[2′-(1-Amino-ethyl)-5′-(pyridin- 4-ylcarbamoyl)-biphenyl-3-carbonyl]-amino}-propionic acid ethyl ester 150

IXa —Me —H

1-{2-[2′-Aminomethyl-5′-(pyridin- 4-ylcarbamoyl)-biphenyl-3-yloxy]-acetyl}-piperidine-4- carboxylic acid ethyl ester 151

IXa —H

Table 9 shows the results for compounds of Formula Xa and Xb.

TABLE 9 Name Cpd Ar —R¹ Formula —R¹² N-[2′-Aminomethyl-5′-(pyridin-4-ylcarbamoyl)-biphenyl-3-yl]-malonamic acid methyl ester 152

—H Xa

6-Aminomethyl-3′-[2-(5-oxo-4,5- dihydro-furan-2-yl)-acetylamino]-biphenyl-3-carboxylic acid pyridin-4- ylamide 153

—H Xa

{[2′-(1-Aminoethyl)-5′-(pyridin-4- ylcarbamoyl)-biphenyl-3-ylcarbamoyl]-methylsulfanyl}-acetic acid ethyl ester 154

—Me Xa

6-(1-Amino-ethyl)-3′-[2-(2-oxo- chroman-4-yl)-acetylamino]-biphenyl-3-carboxylic acid pyridin-4-ylamide 155

—Me Xa

Table 10 shows the results for compounds of Formula XIII.

TABLE 10 Name Cpd Ar —R¹ —R³ —R⁴ ({5-[2-Aminomethyl-5-(pyridin-4-ylcarbamoyl)-phenyl]-thiophene-2- carbonyl}-amino)-acetic acid methylester 156

—H —H

5-[2-Aminomethyl-5-(pyridin-4- ylcarbamoyl)-phenyl]-thiophene-2-carboxylic acid (2-oxo-tetrahydro- thiophen-3-ylmethyl)-amide 157

—H —H

Table 11 shows the results for compounds of Formula XIV, XV, XVI andXVII.

TABLE 11 Name Cpd Ar —R¹ q Formula 4-Aminomethyl-3- (2-oxo-2,3-dihydro-benzofuran-7-yl)- N-pyridin-4-yl- benzamide 158

—H 1 XIV 4-Aminomethyl-3- (2-oxo-2,3-dihydro- benzofuran-6-yl)-N-pyridin-4-yl- benzamide 159

—H 1 XV

Table 12 shows the results for the compounds of Formula XVIIIa.

TABLE 12 Name Cpd Ar —R¹ R²¹ 3-[2′-Aminomethyl-5′-(pyridin-4-ylcarbamoyl)-biphenyl-3-yl]-acrylic acid methyl ester 160

—H —Me Butyric acid 3-[2′-aminomethyl-5′-(pyridin-4-ylcarbamoyl)-biphenyl-3- yl]-acryloyloxymethyl ester 161

—H

Table 13 shows the results for the compounds of Formula XIXa.

TABLE 13 Name Cpd Ar —R¹ R²² 3-[2′-Aminomethyl- 5′-(pyridin-4-ylcarbamoyl)- biphenyl-3-yl]- thioacrylic acid S-ethyl ester 162

—H

3-[2′-Aminomethyl- 5′-(pyridin-4- ylcarbamoyl)- biphenyl-3-yl]-thioacrylic acid S-fluoromethyl ester 163

—H

Table 14 shows the results for the compounds of Formula XXa.

TABLE 14 Name Cpd Ar —R¹ R³ R⁴ {3-[2′-Aminomethyl-5′-(pyridin-4-ylcarbamoyl)-biphenyl-3-yl]- acryloylamino}-acetic acid methyl ester 164

—H —H

Table 15 shows the results for the compounds of Formula XXIa.

TABLE 15 Name Cpd Ar —R¹ Formula R²¹ [2′-(1-Amino-ethyl)-5′-(pyridin-4-ylcarbamoyl)-biphenyl-3-yl]-acetic acid phenyl ester 165

—Me XXIa

Table 16 shows the results for the compounds of Formula XXIIa.

TABLE 16 Name Cpd Ar —R¹ Formula R²¹3-[2′-(1-Amino-ethyl)-5′-(pyridin-4-ylcarbamoyl)-biphenyl-3-yl]-propionic acid propyl ester 166

—Me XXIIa

3-[2′-(1-Amino-ethyl)-5′-(pyridin-4-ylcarbamoyl)-biphenyl-3-yl]-propionic acid phenyl ester 167

—Me XXIIa

Table 17 shows the results for the compounds of Formula XXIIIa.

TABLE 17 Name Cpd Ar —R¹ Formula R²¹ 4-[2-(1-Amino-ethyl)-5-(pyridin-4-ylcarbamoyl)-phenyl]-1H-pyrrole-2- carboxylic acid methyl ester 168

—Me XXIIIa —Me 4-[2-(1-Amino-ethyl)-5-(pyridin-4-ylcarbamoyl)-phenyl]-1H-pyrrole-2- carboxylic acid propyl ester 169

—Me XXIIIa

4-[2-(1-Amino-ethyl)-5-(pyridin-4- ylcarbamoyl)-phenyl]-1H-pyrrole-2-carboxylic acid phenyl ester 170

—Me XXIIIa

Table 18 shows the results for the compounds of Formula XXIVa.

TABLE 18 Name Cpd Ar —R¹ Formula R²¹ 4-[2-(1-Amino-ethyl)-5-(pyridin-4-ylcarbamoyl)-phenyl]-1H-indole-2- carboxylic acid methyl ester 171

—Me XXIVa —Me 4-[2-(1-Amino-ethyl)-5-(pyridin-4-ylcarbamoyl)-phenyl]-1H-indole-2- carboxylic acid propyl ester 172

—Me XXIVa

4-[2-(1-Amino-ethyl)-5-(pyridin-4- ylcarbamoyl)-phenyl]-1H-indole-2-carboxylic acid phenyl ester 173

—Me XXIVa

Additional compounds (Table 19):

TABLE 19 Cpd Structure Formula 174

IIa 175

IIa 176

IIa 177

Va 178

IIa 179

IVa 180

IIa 181

VIIa 182

XXIa 183

IIa 184

IIa 185

IIa 186

IIa 187

IIa 188

IIa 188

IIa 189

IIa 190

XXIa 191

VIIa 192

XXIa 193

XXIa 194

XXIa 195

XXIa 196

IXa 197

VIIa 198

IIa 199

XXIa 200

IIa 201

IIa 202

IIa 203

VIIa 204

XVIIIa 205

IIa 206

IIa 207

IIa 208

XXIa 209

VIIa 210

IIa 211

XXIa 212

XXIa 213

XXIa 214

XXIa 215

XXIa 216

XXIa 217

VIIa 218

VIIa 219

VIIa 220

VIIa 221

VIIa 222

VIIa 223

IIa 224

XXIa

C. In Vitro and In Vivo Assays C.1. ROCK Inhibitory Activity Screening

C.1.1. Kinase Inhibition

Method 1—Proqinase Setup

A ³³P radioisotopic protein kinase assay is used to determine the IC₅₀for inhibiting ROCK II. A final 50 μl reaction cocktail, containing 60mM HEPES-NaOH (pH 7.5), 3 mM MgCl₂, 3 mM MnCl₂, 3 μM Na-orthovanadate,1.2 mM DTT, 1 μM ATP, 50 μg/ml PEG_(20,000), 1% (v/v) DMSO, 1 μM ATP(approx. 3×10⁵ cpm ³³P-γ-ATP), the substrate (Substrate: S6 peptide—2000ng/well) and recombinant protein kinase (0.5 nM—2.5 ng/well) is mixed ona shaker and incubated at 30° C. for 80 minutes. The reaction is stoppedby the addition of 50 μl of a 2% solution of H₃PO₄ and mixed on ashaker. After washing twice with 200 μl of a 0.9% solution of NaCl, thedry plate is counted.

Method 2:

The inhibition assays were performed with a fluorescence polarization(FP) assay using the commercially available ROCK IMAP Kit from MolecularDevices (Product ID. No. R8093), essentially in accordance with theprotocol supplied by the manufacturer. The S6 ribosomal protein-derivedsubstrate used was (FI)-AKRRRLSSLRA, also obtained from MolecularDevices (Product ID No. R7184). The enzyme mix ROCKα/ROCKII was obtainedfrom Upstate Biotechnology (Product ID No 14-451). In summary, allcompounds were screened in the wells of a 384 well plate for enzymaticinhibition with concentrations varying from 100 μM to 0.3 nM using astepwise 3 (or 2)-fold dilution. Y compound (Y-27632 commerciallyavailable from Tocris) was used as a reference (0.4 μM).

To perform the assay, 1 μl of a solution of the compound to be tested inDMSO (at each concentration) was added to 2 μl of a solution of theenzyme in 10 mM Tris-HCl , 10 mM MgCl₂, 0.1% BSA, 0.05% NaN₃, pH 7,2.The final concentration of the enzyme was 2.6 nM.

After incubating for 30 minutes at RT, 2 μl of a mixture of ATP and theprotein substrate in 10 mM Tris-HCl, 10 mM MgCl₂, 0.1% BSA, 0.05% NaN₃,pH 7.2 was added. The final concentration of the ATP was 10 μM and finalconcentration of protein substrate was 0.2 μM.

After incubating for 60 minutes at RT, 12 μl of the IMAP BindingSolution (mix of the IMAP Binding Buffer A (1×) and the IMAP BindingReagent (from the ROCK IMAP kit)) was added.

The mixture thus obtained (total volume: 17 μl) was incubated for 60minutes at RT, upon which the fluorescence polarization was measuredusing an automated plate reader (Perkin Elmer, Model Envision 2100-0010HTS) with FP filters: excitation filter FITC FP 480 and emission filtersFITC FP P-pol 535 and FITC FP S-pol 535 (Perkin-Elmer). The results werefitted to a curve using the XL-Fit algorithm and IC50 values werecalculated for each fitted curve, again using the XL-Fit algorithm.

The IC₅₀ value for the reference compound (Y compound Y-27632) was 0.4μM.

The IC₅₀ values obtained (in accordance with the protocols set forthabove) are represented as follows: “+++” means IC₅₀ below 0.1 μM, “++”means IC50 between 0.1 μM and 1 μM; “+” means IC50 between 1 and 10 μMand “ ” means “not determined yet”.

# Cpds Meth. 1 Meth. 2 1 +++ 2 + 3 4 +++ 5 ++ +++ 6 7 ++ 8 +++ +++ 9 +++10 ++ 11 +++ +++ 12 ++ +++ 13 +++ +++ 14 ++ 15 ++ 16 ++ 17 ++ 18 ++ 19++ 20 + 21 + 22 + 23 + 24 + 25 ++ 26 ++ 27 +++ 28 ++ ++ 29 30 31 ++ 32++ 33 +++ 34 +++ 35 ++ 36 +++ 37 ++ +++ 38 ++ 39 ++ 40 +++ 41 ++ 42 ++43 ++ 44 +++ +++ 45 +++ +++ 46 ++ +++ 47 ++ +++ 48 ++ 49 50 51 52 53 ++54 55 +++ 56 ++ 57 58 +++ +++ 59 +++ 60 ++ +++ 61 ++ 62 +++ 63 ++ 64 +++65 +++ +++ 66 67 +++ 68 +++ 69 +++ 70 +++ +++ 71 ++ ++ 72 +++ 73 +++ 74++ 75 +++ 76 ++ 77 +++ 78 +++ 79 +++ 80 ++ 81 +++ 82 +++ 83 ++ 84 ++ 85++ 86 +++ 87 ++ 88 +++ ++ 89 ++ 90 +++ ++ 91 ++ 92 ++ 93 +++ 94 ++ 95 ++96 +++ 97 +++ 98 99 100 101 +++ 102 +++ 103 104 105 +++ 106 +++ 107 108109 110 111 112 +++ 113 ++ 114 115 116 117 118 119 120 121 122 + 123124 + 125 126 127 + 128 129 130 +++ 131 ++ ++ 132 133 134 ++ +++ 135 136++ 137 ++ 138 139 140 141 ++ 142 ++ 143 ++ 144 145 146 147 +++ 148 149150 151 152 153 154 +++ 155 +++ 156 157 158 159 160 161 162 163 164 165166 ++ ++ 167 ++ +++ 168 ++ ++ 169 +++ 170 ++ +++ 171 ++ 172 ++ ++ 173++ 174 ++ 175 +++ 176 +++ 177 ++ 178 ++ 179 ++ 180 ++ 181 + 182 ++ 183++ 184 ++ 185 ++ 186 187 ++ 188 + 189 ++ 190 ++ 191 ++ 192 + 193 ++194 + 195 + 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210211 212 213 214 215 216 217 218 219 220 221 222 223 224

C.1.2. Activity Against ROCK in a Cellular Assay Using LPS-StimulatedPBMC in the Absence and Presence of Plasma

To ensure the stimulation of PBMC by LPS, the medium is enriched withLPS-binding protein (LBP) that will facilitate the delivery of LPS tothe CD14 receptor and enhance the LPS-induced immune response. Cytokinessecreted by activated PBMC include TNF, which is detected by means of acolorimetric ELISA. In the presence of an active compound, the releaseof TNF is inhibited in a concentration-dependent manner. Subsequently acontrol assay using the same set up in the presence of plasma isincluded.

For example compound 46 showed IC₅₀ 120 nM (assay without plasma)whereas is inactive (IC₅₀>10 μM) in the presence of plasma.

C.1.3. Smooth Muscle Relaxing Activity of Generated Soft ROCK InhibitorsIn Vitro Using Organ Baths of Guinea Pig Trachea

Guinea pig trachea rings are prepared and incubated with a fixedconcentration of the bronchoconstrictive agent carbachol. Then,increasing concentrations of the soft ROCK inhibitors are added and thecontractive properties of the trachea measured for each of the compoundconcentrations. The study set-up allows the determination of an IC₅₀,represented by the concentration of compound that induces a force equalto 50% of that observed for the vehicle-treated trachea.

In addition retention on the target is assessed using the abovedescribed organ baths of guinea pig trachea. In brief, upon induction ofmaximal relaxation with the ROCK inhibitors, trachea rings arethoroughly washed. Then, carbachol is added again and contractiveproperties are measured to determine whether the inhibitory activity ofthe ROCK inhibitors is prolonged upon the washout. A prolongedinhibitory activity after the washout is highly indicative for aprolonged retention of the compound at the lungs in vivo.

For example compound 46 showed IC₅₀ of 500 nM.

C.2. Pharmacological Characterization

C.2.1. Stability Assay in Human and/or Rat Plasma

Compounds are incubated at a concentration of 1 μM in rat (mice orrabbit) or human plasma. Samples are taken at fixed time points and theremnant of compound is determined by LC-MS/MS after proteinprecipitation. Half life is expressed in minutes.

t½ t½ rat human # Cpd plasma plasma 46 5.8 1.9 47 4.5 9.8 97 38 44 137<1 1.9

i) C.2.2. Stability Towards Drug Metabolizing Enzymes in Lung S9

A 1 μM solution of the ROCK inhibitors is incubated with a reactionmixture containing lung S9 (from smokers) as well as the cofactorsNADPH, UDPGA, PAPS and GSH. Samples are collected at 0, 15, 30 and 60minutes post incubation. Negative control samples incubated with ROCKinhibitors and S9 fraction in the absence of cofactors are run inparallel. By using LC-MS/MS analysis, the percent of ROCK compoundsremaining at each time point, the metabolic half-life of the ROCKcompounds (expressed in minutes) and the metabolic half-life of thecontrol compounds are determined.

t½ human lung # Cpd S9 46 53 47 >60 65 >60

i) C.2.3. Stability Assay in Rabbit Aqueous Humor

Compounds are incubated at a concentration of 1 μM in rabbit aqueoushumor (AH). Samples are taken at fixed time points and the remnant ofcompound is determined by LC-MS/MS after protein precipitation.

# Cpd t½ rabbits AH 46 >60 169 >60

i) C.2.4. Kinetic Binding Characterization

The assay is based on a reporter displacement binding technology. Itinvolves the use a probe specific for the ATP-binding site of ROCK. Asignal is generated when the probe is bound to the active site. In thepresence of a ATP competitive ROCK inhibitor, the probe is displacedfrom the enzyme and the signal is disrupted. The probe displacement ismonitored over time and the Kon and Koff constants are determined.Inhibitor mechanism of action is characterized enzymatically using thefluorescence-based OMNIA technology.

C.2.5. Anti-Inflammatory Activity of Generated Soft ROCK Inhibitors inan Acute LPS Lung Challenge Model in Mice

Half an hour after intranasal compound administration, mice arechallenged intratracheally with LPS. Twenty-four hours later, the miceare sacrificed, bronchoalveolar lavage fluid (BALF) collected and totalcell number as well as percentage neutrophils determined.Anti-inflammatory activity is represented by a reduction in the totalnumber of BALF cells and in the number of neutrophils as compared to anon-treated control group).

i) C.2.6. Intraocular Pressure (IOP) Lowering in Normotensive Rats orRabbits

In normotensive rats, the IOP is measured using a Tonolab tonometer. Asthe IOP is in the range of 8-12 mmHg (with a mean around 10), a maximumdecrease of 3 mmHg is usually observed. Timolol (β-blocker), clonidine(α-agonist) and brimonidine (α2-agonist) decrease the IOP by 2-3 mmHg.In normotensive rabbits, the IOP is in the range of 15-20 mmHg (with amean around 18), again giving a maximum decrease of 3-4 mmHg.

1. A method for the prevention and/or treatment of an eye disease ordisorder selected from the group consisting of retinopathy, opticneuropathy, glaucoma, inflammatory eye diseases and degenerative retinaldiseases, comprising: administering a compound of Formula IIaa or astereoisomer, tautomer, racemic, salt, hydrate, or solvate thereof to asubject,

Wherein X is hydrogen or fluoro; R¹ represents hydrogen or C₁₋₄alkyl;R²¹ is selected from C₁₋₆alkyl, 3,4-dihydro-1(2H)-benzopyranylsubstituted with oxo, and phenyl.
 2. The method of claim 1 wherein X ishydrogen.
 3. The method of claim 1 wherein X is fluoro.
 4. The method ofclaim 1, wherein R²¹ is selected from: methyl; ethyl; n-propyl;i-propyl; butyl and its isomers; pentyl and its isomers; hexyl and itsisomers; cyclopentyl; 2-, 3-, or 4-methylcyclopentyl;cyclopentylmethylene; cyclohexyl; 3,4-dihydro-1(2H)-benzopyranylsubstituted with oxo; and phenyl.
 5. The method of claim 1, wherein saidcompound is selected from the group consisting of:2′-Aminomethyl-5′-(pyridin-4-ylcarbamoyl)-biphenyl-3-carboxylic acidmethyl ester,2′-(1-Amino-ethyl)-5′-(pyridin-4-ylcarbamoyl)-biphenyl-3-carboxylic acidmethyl ester,2′-Aminomethyl-5′-(pyridin-4-ylcarbamoyl)-biphenyl-3-carboxylic acidethyl ester,2′-(1-Amino-ethyl)-5′-(pyridin-4-ylcarbamoyl)-biphenyl-3-carboxylic acidethyl ester,2′-Aminomethyl-5′-(pyridin-4-ylcarbamoyl)-biphenyl-3-carboxylic acidpropyl ester,2′-(1-Amino-ethyl)-5′-(pyridin-4-ylcarbamoyl)-biphenyl-3-carboxylic acidpropyl ester,2′-(1-Amino-ethyl)-5′-(3-fluoro-pyridin-4-ylcarbamoyl)-biphenyl-3-carboxylicacid propyl ester,2′-(1-Amino-ethyl)-5′-(pyridin-4-ylcarbamoyl)-biphenyl-3-carboxylic acidbutyl ester,2′-Aminomethyl-5′-(pyridin-4-ylcarbamoyl)-biphenyl-3-carboxylic acidbutyl ester,2′-(1-Amino-ethyl)-5′-(pyridin-4-ylcarbamoyl)-biphenyl-3-carboxylic acidisopropyl ester,2′-(1-Amino-ethyl)-5′-(pyridin-4-ylcarbamoyl)-biphenyl-3-carboxylic acidcyclopropylmethyl ester, and2′-Aminomethyl-5′-(pyridin-4-ylcarbamoyl)-biphenyl-3-carboxylic acidcyclopentylmethyl ester.
 6. The method of claim 1, wherein said compoundis selected from the group consisting of:2′-(1-Amino-ethyl)-5′-(3-fluoro-pyridin-4-ylcarbamoyl)-biphenyl-3-carboxylicacid methyl ester,2′-(1-Amino-ethyl)-5′-(3-fluoro-pyridin-4-ylcarbamoyl)-biphenyl-3-carboxylicacid ethyl ester,2′-(1-Amino-ethyl)-5′-(3-fluoro-pyridin-4-ylcarbamoyl)-biphenyl-3-carboxylicacid cyclopropylmethyl ester, propyl3-[2-(aminomethyl)-5-[(3-fluoropyridin-4-yl)carbamoyl]phenyl]benzoate,cyclobutylmethyl3-[2-(aminomethyl)-5-[(3-fluoropyridin-4-yl)carbamoyl]phenyl]benzoate,cyclopentylmethyl3-[2-(aminomethyl)-5-[(3-fluoropyridin-4-yl)carbamoyl]phenyl]benzoate,and cyclopropylmethyl3-[2-(aminomethyl)-5-[(3-fluoropyridin-4-yl)carbamoyl]phenyl]benzoate.7. A method for the prevention and/or treatment of an eye disease ordisorder selected from the group consisting of retinopathy, opticneuropathy, glaucoma, inflammatory eye diseases and degenerative retinaldiseases comprising: administering a pharmaceutical composition to asubject in need of treatment, said composition comprising a compound ofFormula IIaa or a stereoisomer, tautomer, racemic, salt, hydrate, orsolvate thereof,

Wherein X is hydrogen or fluoro; R¹ represents hydrogen or C₁₋₄alkyl;R²¹ is selected from C₁₋₆alkyl, 3,4-dihydro-1(2H)-benzopyranylsubstituted with oxo, and phenyl.
 8. The method of claim 1 wherein saideye disease or disorder is an inflammatory eye disease or disorder. 9.The method of claim 1 wherein said eye disease or disorder is glaucoma.10. The method of claim 7 wherein said eye disease or disorder is aninflammatory eye disease or disorder.
 11. The method of claim 7 whereinsaid eye disease or disorder is glaucoma.